Disease Information

General Information of the Disease (ID: DIS00062)

Name	Osteosarcoma
ICD	ICD-11: 2B51
Resistance Map

Type(s) of Resistant Mechanism of This Disease

DISM: Drug Inactivation by Structure Modification

EADR: Epigenetic Alteration of DNA, RNA or Protein

IDUE: Irregularity in Drug Uptake and Drug Efflux

MRAP: Metabolic Reprogramming via Altered Pathways

RTDM: Regulation by the Disease Microenvironment

UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s)

5 drug(s) in total

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Bortezomib

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-101				[2]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Proteasome maturation protein (POMP)				[2]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Carboplatin

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-34a-5p				[3]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Carboplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
In Vitro Model	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Annexin V-FITC/propidium iodide (PI) staining assay
Mechanism Description	The miR34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene.
Key Molecule: hsa-miR-199a-3p				[4]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Carboplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
Cell Pathway Regulation	NF-kappaB signaling pathway		Inhibition	hsa04064
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The Ak4 gene is one of the targets of miR-199a-3p and negatively correlates with the effect of miR-199a-3p on OS drug-resistance.
Key Molecule: hsa-miR-34a-5p				[5]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Carboplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	MEF2 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
	MG63.2 cells	Bone	Homo sapiens (Human)	CVCL_R705
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Type-1 angiotensin II receptor (AGTR1)				[3]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Carboplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
In Vitro Model	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Annexin V-FITC/propidium iodide (PI) staining assay
Mechanism Description	The miR34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene.
Key Molecule: Adenylate kinase 4 (AK4)				[4]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Carboplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
Cell Pathway Regulation	NF-kappaB signaling pathway		Inhibition	hsa04064
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis; RIP assay; Luciferase reporter assay
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The Ak4 gene is one of the targets of miR-199a-3p and negatively correlates with the effect of miR-199a-3p on OS drug-resistance.
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT)				[5]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Carboplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	MEF2 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
	MG63.2 cells	Bone	Homo sapiens (Human)	CVCL_R705
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.

Cisplatin

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: OIP5 antisense RNA 1 (OIP5-AS1)				[6]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
	PI3K/AKT/mTOR signaling pathway		Activation	hsa04151
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	OIP5-AS1 regulates cisplatin resistance by activating the PI3k/AkT/mTOR signaling pathway.
Key Molecule: hsa-miR-340-5p				[6]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
	PI3K/AKT/mTOR signaling pathway		Activation	hsa04151
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	OIP5-AS1 regulates cisplatin resistance by activating the PI3k/AkT/mTOR signaling pathway.
Key Molecule: hsa-miR-34a-5p				[3], [7]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ATF2/ATF3/ATF4 signaling pathway		Inhibition	hsa04915
In Vitro Model	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Annexin V-FITC/propidium iodide (PI) staining assay
Mechanism Description	The miR34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene. And miR34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene.
Key Molecule: Delta-like protein 1 (DLL1)				[7]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ATF2/ATF3/ATF4 signaling pathway		Inhibition	hsa04915
In Vitro Model	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
	MG63.2 cells	Bone	Homo sapiens (Human)	CVCL_R705
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	IC50 assay; Flow cytometric analysis
Mechanism Description	miR34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene. The activity of the ATF2/ATF3/ATF4 pathway was reduced in the miR34a-5p mimic-transfected G-292 cells but increased in the miR34a-5p antagomiRtransfected SJSA-1 cells, hence the ATF2/ATF3/ATF4 pathway was validated to be involved in the OS chemoresistance mediated by miR34a-5p.
Key Molecule: hsa-miR-199a-3p				[4]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	NF-kappaB signaling pathway		Inhibition	hsa04064
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The Ak4 gene is one of the targets of miR-199a-3p and negatively correlates with the effect of miR-199a-3p on OS drug-resistance.
Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1)				[8]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	BCL2/cyclin D1 signaling pathway		Inhibition	hsa04210
	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	The miR-34c inhibitor restored the BCL-2 and cyclin D1 levels in MG63 and HOS cell line, which implicated that NEAT1 inhibited the tumor suppressor miR-34c and up-regulated cell survival signals for the development of OS.
Key Molecule: hsa-mir-377				[9]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	MG63/CDDP cells	Bone	Homo sapiens (Human)	CVCL_0426
	SAOS-2/CDDP cells	Bone	Homo sapiens (Human)	CVCL_0548
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	XIAP overexpression greatly cancelled the apoptosis promoting the effect of miR377 in Saos-2/CDDP cell.
Key Molecule: hsa_circ_PVT1				[10]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell colony		Activation	hsa05200
	Cell viability		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	KHOS cells	Bone	Homo sapiens (Human)	CVCL_2546
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Colony formation assay
Mechanism Description	CircPVT1 knockdown reduces the expression of classical multidrug resistance related gene-ABCB1 in OS cells.
Key Molecule: hsa-mir-340				[11]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Overexpression of ZEB1 reversed the miR-340-induced alleviation of chemoresistance in drug-resistant OS cells.
Key Molecule: hsa-miR-34a-5p				[5]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	MEF2 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
	MG63.2 cells	Bone	Homo sapiens (Human)	CVCL_R705
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.
Key Molecule: hsa-miR-146b-5p				[12]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	Wnt/Beta-catenin signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	hFOB1.19 cells	Fetal bone	Homo sapiens (Human)	CVCL_3708
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	miR-146b-5p was highly expressed in human osteosarcoma tissues and an elevated expression of miR-146b-5p was observed in human osteosarcoma tissues after chemotherapy. Furthermore, it was shown that miR-146b-5p overexpression promoted migration and invasiveness. miR-146b-5p overexpression also increased resistance to chemotherapy. Moreover, knockdown of miR-146b-5p substantially inhibited migration and invasion of osteosarcoma cells as well as rendered them significantly more sensitive to chemotherapy. Results of western blot assay indicated that miR-146b-5p increased MMP-16 protein expression and showed a decrease of ZNRF3 protein. Whereas, IWR-1-endo, an inhibitor of Wnt/beta-catenin, suppressed the decrease in apoptosis of osteosarcoma cells caused by miR-146b-5p overexpression. These results indicated that miR-146b-5p promoted proliferation, migration and invasiveness.
Key Molecule: hsa-mir-33a				[13]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	TUNEL assay
Mechanism Description	miR-33a is up-regulated in chemoresistant OS and that the miR-33a level is negatively correlated with the TWIST protein level in OS. miR-33a promotes OS cell resistance to cisplatin by down-regulating TWIST.
Key Molecule: hsa-mir-221				[14]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	PI3K/AKT signaling pathway		Regulation	N.A.
In Vitro Model	SOSP-9607 cells	Bones	Homo sapiens (Human)	CVCL_4V80
	SOSP-9901 cells	Bones	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	qRT-PCR; RT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-221 induce cell survival and cisplatin resistance in human osteosarcoma at least partly through targeting the PI3k/PTEN/Akt pathway.
Key Molecule: hsa-miR-203a-3p				[15]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The most upregulated circRNA, miRNA, and mRNA were hsa_circ_0004674 (17-fold change), hsa-miR-337-3p (12-fold change), and C6orf106 (124-fold change), respectively. The most downregulated circRNA, miRNA, and mRNA were hsa_circ_0068458 (12-fold change), hsa-miR-203a-3p (10-fold change), and AKR1C2 (197-fold change), respectively.
Key Molecule: hsa-miR-337-3p				[15]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The most upregulated circRNA, miRNA, and mRNA were hsa_circ_0004674 (17-fold change), hsa-miR-337-3p (12-fold change), and C6orf106 (124-fold change), respectively. The most downregulated circRNA, miRNA, and mRNA were hsa_circ_0068458 (12-fold change), hsa-miR-203a-3p (10-fold change), and AKR1C2 (197-fold change), respectively.
Key Molecule: LINC00520				[16]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	METTL3/LINC00520/ENO1/glycolysis axis		Regulation	N.A.
In Vitro Model	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
Mechanism Description	LINC00520 was identified as a novel cisplatin resistance-related lncRNA in osteosarcoma, and its high expression was associated with poor prognosis of osteosarcoma patients. Functionally, LINC00520 could potentiate osteosarcoma resistance to cisplatin in vitro and in vivo. Mechanistically, LINC00520 bound to ENO1 and upregulated ENO1 protein expression by blocking FBXW7-mediated ENO1 ubiquitination and proteasomal degradation, thereby promoting glycolysis and ultimately inducing cisplatin resistance in osteosarcoma. Furthermore, METTL3 could stabilize and upregulate LINC00520 in an m6A-YTHDF2-dependent manner in osteosarcoma. This study proposes a novel lncRNA-driven mechanism for cisplatin resistance in osteosarcoma, and offers a promising therapeutic strategy for reversing chemoresistance in osteosarcoma by targeting the METTL3/LINC00520/ENO1/glycolysis axis.
Key Molecule: hsa-miR-29b-1				[17]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Bcl-2/IAP-2 signalling pathway		Regulation	N.A.
	Oct3/4-Sox2-Nanog/CD133-N-Myc signalling pathway		Regulation	N.A.
	CCND2-E2F1/E2F2-Rb signalling pathway		Regulation	N.A.
Experiment for Molecule Alteration	RT-PCR; Western blot
Experiment for Drug Resistance	Growth curve and cell viability assays; Cell cycle and proliferation analyses; Flow cytometry; Sarcosphere and colony formation assay; Chemosensitivity analysis; Scratch/wound-healing and in vitro matrigel invasion assay
Mechanism Description	These data suggest that miR-29b-1 may negatively regulate the expression of these markers and that its overexpression probably affects cell proliferation, self-renewal and chemosensitivity of 3AB-OS CSCs by directly or indirectly targeting their mRNAs.
Key Molecule: hsa-miR-339				[16]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	miR-339-3p/IGF1R		Regulation	N.A.
In Vitro Model	HFOB cells	Bone	Homo sapiens (Human)	CVCL_3708
	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR; Western blot; Immunohistochemistry; Luciferase reporter assay; RIP experiments
Experiment for Drug Resistance	CCK8 assay; Colony formation assay; Flow cytometry analysis
Mechanism Description	Moreover, we performed apoptosis assays to reveal the regulatory effects of the circDOCK1/miR-339-3p/IGF1R axis on cisplatin sensitivity
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1)				[10]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell colony		Activation	hsa05200
	Cell viability		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	KHOS cells	Bone	Homo sapiens (Human)	CVCL_2546
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Colony formation assay
Mechanism Description	CircPVT1 knockdown reduces the expression of classical multidrug resistance related gene-ABCB1 in OS cells.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Interleukin-24 (IL24)				[18]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ZBTB7A/LINC00473/IL24 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	RT-PCR; Dual-Luciferase reporter assay
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	LINC00473 promoted the activity of IL24 promoter and elevated IL24 expression. LINC00473 interacts with the transcript factor C/EBPbeta, facilitating its binding to the promoter of IL24, leading to decrease chemoresistance. The ZBTB7A-LINC00473-IL24 signaling axis plays an important role in regulating osteosarcoma chemoresistance.
Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A)				[18]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ZBTB7A/LINC00473/IL24 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Elevated ZBTB7A inhibits cisplatin-induced apoptosis by repressing LINC00473 expression. The ZBTB7A-LINC00473-IL24 signaling axis plays an important role in regulating osteosarcoma chemoresistance.
Key Molecule: Type-1 angiotensin II receptor (AGTR1)				[3]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Annexin V-FITC/propidium iodide (PI) staining assay
Mechanism Description	The miR34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene.
Key Molecule: Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2)				[19]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell colony		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Ckk-8 assay; Colony formation assay; Annexin V-FITC staining assay
Mechanism Description	Long non-coding RNA LINC00161 sensitises osteosarcoma cells to cisplatin-induced apoptosis by regulating the miR645-IFIT2 axis. LINC00161 upregulated IFIT2 expression via miR645.
Key Molecule: Adenylate kinase 4 (AK4)				[4]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	NF-kappaB signaling pathway		Inhibition	hsa04064
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis; RIP assay; Luciferase reporter assay
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The Ak4 gene is one of the targets of miR-199a-3p and negatively correlates with the effect of miR-199a-3p on OS drug-resistance.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[8]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	BCL2/cyclin D1 signaling pathway		Inhibition	hsa04210
	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	The miR-34c inhibitor restored the BCL-2 and cyclin D1 levels in MG63 and HOS cell line, which implicated that NEAT1 inhibited the tumor suppressor miR-34c and up-regulated cell survival signals for the development of OS.
Key Molecule: G1/S-specific cyclin-D1 (CCND1)				[8]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	BCL2/cyclin D1 signaling pathway		Inhibition	hsa04210
	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	The miR-34c inhibitor restored the BCL-2 and cyclin D1 levels in MG63 and HOS cell line, which implicated that NEAT1 inhibited the tumor suppressor miR-34c and up-regulated cell survival signals for the development of OS.
Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP)				[9]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	MG63/CDDP cells	Bone	Homo sapiens (Human)	CVCL_0426
	SAOS-2/CDDP cells	Bone	Homo sapiens (Human)	CVCL_0548
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	XIAP overexpression greatly cancelled the apoptosis promoting the effect of miR377 in Saos-2/CDDP cell.
Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1)				[11]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Overexpression of ZEB1 reversed the miR-340-induced alleviation of chemoresistance in drug-resistant OS cells.
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT)				[5]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	MEF2 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
	MG63.2 cells	Bone	Homo sapiens (Human)	CVCL_R705
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.
Key Molecule: E3 ubiquitin-protein ligase ZNRF3 (ZNRF3)				[12]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	Wnt/Beta-catenin signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	hFOB1.19 cells	Fetal bone	Homo sapiens (Human)	CVCL_3708
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	miR-146b-5p was highly expressed in human osteosarcoma tissues and an elevated expression of miR-146b-5p was observed in human osteosarcoma tissues after chemotherapy. Furthermore, it was shown that miR-146b-5p overexpression promoted migration and invasiveness. miR-146b-5p overexpression also increased resistance to chemotherapy. Moreover, knockdown of miR-146b-5p substantially inhibited migration and invasion of osteosarcoma cells as well as rendered them significantly more sensitive to chemotherapy. Results of western blot assay indicated that miR-146b-5p increased MMP-16 protein expression and showed a decrease of ZNRF3 protein. Whereas, IWR-1-endo, an inhibitor of Wnt/beta-catenin, suppressed the decrease in apoptosis of osteosarcoma cells caused by miR-146b-5p overexpression. These results indicated that miR-146b-5p promoted proliferation, migration and invasiveness.
Key Molecule: Twist-related protein 1 (TWST1)				[13]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	TUNEL assay
Mechanism Description	miR-33a is up-regulated in chemoresistant OS and that the miR-33a level is negatively correlated with the TWIST protein level in OS. miR-33a promotes OS cell resistance to cisplatin by down-regulating TWIST.
Key Molecule: Phosphatase and tensin homolog (PTEN)				[14]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	PI3K/AKT signaling pathway		Regulation	N.A.
In Vitro Model	SOSP-9607 cells	Bones	Homo sapiens (Human)	CVCL_4V80
	SOSP-9901 cells	Bones	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-221 induce cell survival and cisplatin resistance in human osteosarcoma at least partly through targeting the PI3k/PTEN/Akt pathway.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-34				[20]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Bim signaling pathway		Activation	hsa05206
Cell Pathway Regulation	c-Myc signaling pathway		Activation	hsa05230
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis
Mechanism Description	miR34a increases cisplatin sensitivity of osteosarcoma cells in vitro through up-regulation of c-Myc and Bim signal.
Key Molecule: hsa-mir-200c				[21]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell migration		Inhibition	hsa04670
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR; RT-qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometric analysis; Caspase-3 Activity Assay
Mechanism Description	miR200c regulates tumor growth and chemosensitivity to cisplatin in osteosarcoma by targeting AkT2 and inhibiting the activity of cell proliferation and cell migration.
Key Molecule: Long non-protein coding RNA (LINC00473)				[18]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ZBTB7A/LINC00473/IL24 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	LINC00473 promoted the activity of IL24 promoter and elevated IL24 expression. LINC00473 interacts with the transcript factor C/EBPbeta, facilitating its binding to the promoter of IL24, leading to decrease chemoresistance. The ZBTB7A-LINC00473-IL24 signaling axis plays an important role in regulating osteosarcoma chemoresistance.
Key Molecule: hsa-mir-491				[22]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR; RT-qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	Overexpression of miR491 inhibits chemoresistance and suppresses OS cell lung metastasis, whereas it enhances cisplatin (CDDP)-induced tumor growth inhibition and apoptosis, miR491 exerts its role by directly targeting alphaB-crystallin (CRYAB) in OS.
Key Molecule: hsa-miR-340-5p				[23]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	MG63/CDDP cells	Bone	Homo sapiens (Human)	CVCL_0426
	SAOS-2/CDDP cells	Bone	Homo sapiens (Human)	CVCL_0548
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Annexin V-FITC apoptosis assay
Mechanism Description	microRNA-340-5p modulates cisplatin resistance by targeting LPAATbeta in osteosarcoma.
Key Molecule: hsa-mir-410				[24]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HFob 1.19	Bone	Homo sapiens (Human)	CVCL_3708
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	microRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma, miR410 directly decreased ATG16L1 expression by targeting its 3'-untranslated region.
Key Molecule: hsa-miR-199a-5p				[25]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR199a-5p directly targeted Beclin1 and negatively mediated Beclin1 expression at a post-transcriptional level, microRNA-199a-5p inhibits cisplatin-induced drug resistance via inhibition of autophagy in osteosarcoma cells.
Key Molecule: hsa-miR-422a				[26]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Inhibition	hsa05200
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HFOB cells	Bone	Homo sapiens (Human)	CVCL_3708
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis of apoptosis; Transwell assay
Mechanism Description	Overexpression of miR422a inhibits cell proliferation and invasion, and enhances chemosensitivity by directly targeting TGFbeta2 in osteosarcoma cells.
Key Molecule: hsa-mir-381				[27]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	mTOR signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Matrigel chamber invasion assay
Mechanism Description	There is a strong negative correlation between the expression of miR381 and LRRC4, suppressing the expression of miR381 increases the sensitivity of OS cells to chemotherapeutic drugs through the LRRC4-mediated mTOR pathway.
Key Molecule: Long non-protein coding RNA 161 (LINC00161)				[19]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	Ckk-8 assay; Colony formation assay; Annexin V-FITC staining assay
Mechanism Description	Long non-coding RNA LINC00161 sensitises osteosarcoma cells to cisplatin-induced apoptosis by regulating the miR645-IFIT2 axis. LINC00161 acted as a miR645 sponge and inhibited its activity.
Key Molecule: hsa-miR-645				[19]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	Ckk-8 assay; Colony formation assay; Annexin V-FITC staining assay
Mechanism Description	Long non-coding RNA LINC00161 sensitises osteosarcoma cells to cisplatin-induced apoptosis by regulating the miR645-IFIT2 axis. LINC00161 acted as a miR645 sponge and inhibited its activity.
Key Molecule: CDKN2B antisense RNA 1 (CDKN2B-AS1)				[28]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell colony		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	ANRIL-silenced cells were more sensitive to cisplatin and the expression level of miR-125a-5p was elevated in ANRIL-silenced cells.
Key Molecule: hsa-miR-125a-5p				[28]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell colony		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	ANRIL-silenced cells were more sensitive to cisplatin and the expression level of miR-125a-5p was elevated in ANRIL-silenced cells.
Key Molecule: hsa-mir-92a				[29]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell viability		Inhibition	hsa05200
	Notch1 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	HFOB cells	Bone	Homo sapiens (Human)	CVCL_3708
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay; Transwell assay
Mechanism Description	miR-92a inhibited cell growth, migration, and enhanced cisplatin sensitivity of OS cell by downregulating Notch1.
Key Molecule: hsa-mir-34c				[8]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	BCL2/cyclin D1 signaling pathway		Inhibition	hsa04210
	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	The miR-34c inhibitor restored the BCL-2 and cyclin D1 levels in MG63 and HOS cell line, which implicated that NEAT1 inhibited the tumor suppressor miR-34c and up-regulated cell survival signals for the development of OS.
Key Molecule: hsa-mir-22				[30]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-22 overexpression sensitizes MG-63 cells to cisplatin treatment and reduces the expression of S100A11.
Key Molecule: hsa-mir-223				[31]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
	JNk signaling pathway		Activation	hsa04010
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	Sk-ES-1 cells	Bone	Homo sapiens (Human)	CVCL_0627
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	miR-223 overexpression could sensitize OS cell lines to CDDP and Hsp70 protein levels were remarkably reduced by miR-223 overexpression whereas increased by miR-223 inhibition.
Key Molecule: hsa-mir-21				[32]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
	HLNG cells	Bone marrow	Homo sapiens (Human)	N.A.
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Northern blot analysis
Experiment for Drug Resistance	Scratch assay
Mechanism Description	miR-21 regulatory network plays a role in tumorigenesis of osteosarcoma. Its expression facilitates cell proliferation and decreases cellular sensitivity towards cisplatin. Both effects can be rescued by Spry2, a target protein downregulated by increased miR-21 levels.
Key Molecule: hsa-mir-138				[33]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	miR138/EZH2 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
In Vivo Model	BALB/c nu/nu nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-138 acts as a tumor suppressor in osteosarcoma, inhibiting cell proliferation, migration, and invasion by downregulating EZH2 expression. Mir-138 overexpression also enhances osteosarcoma cell chemosensitivity to cisplatin by targeting EZH2.
Key Molecule: hsa-mir-125b				[34]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	p53/p38/MAPK signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Overexpression of miR-125b inhibited proliferation, migration, and invasion of OS cells and reduced the chemotherapy resistance of OS cells to cisplatin by targeting Bcl-2.
Key Molecule: hsa-mir-382				[35]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.
Key Molecule: hsa-mir-29b				[36]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	3AB-OS CSC cells	Bone marrow	Homo sapiens (Human)	CVCL_LM95
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	Trypan blue assay; Flow cytometry assay
Mechanism Description	miR-29b-1 overexpression sensitized 3AB-OS cells to chemotherapeutic drug-induced apoptosis miR-29b-1 negatively regulated the expression of Bcl-2.
Key Molecule: hsa-mir-103				[37]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	Survival assay/crystal violet staining assay
Mechanism Description	miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.
Key Molecule: hsa-miR-107				[37]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	Survival assay/crystal violet staining assay
Mechanism Description	miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.
Key Molecule: hsa-mir-96				[38]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	Overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: RAC-beta serine/threonine-protein kinase (AKT2)				[21]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell migration		Inhibition	hsa04670
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Luciferase reporter assay
Experiment for Drug Resistance	CCK8 assay; Flow cytometric analysis; Caspase-3 Activity Assay
Mechanism Description	miR200c regulates tumor growth and chemosensitivity to cisplatin in osteosarcoma by targeting AkT2 and inhibiting the activity of cell proliferation and cell migration.
Key Molecule: Alpha-crystallin B chain (CRYAB)				[22]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR; Luciferase reporter assay; Western blot analysis; Western blot analysis; Immunohistochemistry assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	Overexpression of miR491 inhibits chemoresistance and suppresses OS cell lung metastasis, whereas it enhances cisplatin (CDDP)-induced tumor growth inhibition and apoptosis, miR491 exerts its role by directly targeting alphaB-crystallin (CRYAB) in OS.
Key Molecule: Lysophosphatidic acid acyltransferase beta (AGPAT2)				[23]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	MG63/CDDP cells	Bone	Homo sapiens (Human)	CVCL_0426
	SAOS-2/CDDP cells	Bone	Homo sapiens (Human)	CVCL_0548
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Annexin V-FITC apoptosis assay
Mechanism Description	microRNA-340-5p modulates cisplatin resistance by targeting LPAATbeta in osteosarcoma.
Key Molecule: Autophagy-related protein 16-1 (ATG16L1)				[24]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HFob 1.19	Bone	Homo sapiens (Human)	CVCL_3708
Experiment for Molecule Alteration	Luciferase reporter assay; Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	microRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma, miR410 directly decreased ATG16L1 expression by targeting its 3'-untranslated region.
Key Molecule: Beclin-1 (BECN1)				[25]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR199a-5p directly targeted Beclin1 and negatively mediated Beclin1 expression at a post-transcriptional level, microRNA-199a-5p inhibits cisplatin-induced drug resistance via inhibition of autophagy in osteosarcoma cells.
Key Molecule: Transforming growth factor beta-2 proprotein (TGFB2)				[26]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Inhibition	hsa05200
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HFOB cells	Bone	Homo sapiens (Human)	CVCL_3708
Experiment for Molecule Alteration	Western blot analysis; Dual luciferase activity assay
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis of apoptosis; Transwell assay
Mechanism Description	Overexpression of miR422a inhibits cell proliferation and invasion, and enhances chemosensitivity by directly targeting TGFbeta2 in osteosarcoma cells.
Key Molecule: Leucine-rich repeat-containing protein 4 (LRRC4)				[27]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	mTOR signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Matrigel chamber invasion assay
Mechanism Description	There is a strong negative correlation between the expression of miR381 and LRRC4, suppressing the expression of miR381 increases the sensitivity of OS cells to chemotherapeutic drugs through the LRRC4-mediated mTOR pathway.
Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1)				[29]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell viability		Inhibition	hsa05200
	Notch1 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	HFOB cells	Bone	Homo sapiens (Human)	CVCL_3708
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay; Transwell assay
Mechanism Description	miR-92a inhibited cell growth, migration, and enhanced cisplatin sensitivity of OS cell by downregulating Notch1.
Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1)				[8]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	BCL2/cyclin D1 signaling pathway		Inhibition	hsa04210
	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	The miR-34c inhibitor restored the BCL-2 and cyclin D1 levels in MG63 and HOS cell line, which implicated that NEAT1 inhibited the tumor suppressor miR-34c and up-regulated cell survival signals for the development of OS.
Key Molecule: Protein S100-A11 (S100A11)				[30]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-22 overexpression sensitizes MG-63 cells to cisplatin treatment and reduces the expression of S100A11.
Key Molecule: Heat shock 70 kDa protein 1A (HSP70)				[31]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
	JNk signaling pathway		Activation	hsa04010
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	Sk-ES-1 cells	Bone	Homo sapiens (Human)	CVCL_0627
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	miR-223 overexpression could sensitize OS cell lines to CDDP and Hsp70 protein levels were remarkably reduced by miR-223 overexpression whereas increased by miR-223 inhibition.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[34], [36]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	p53/p38/MAPK signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	3AB-OS CSC cells	Bone marrow	Homo sapiens (Human)	CVCL_LM95
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR; Western blot analysis
Experiment for Drug Resistance	Trypan blue assay; Flow cytometry assay; CCK8 assay
Mechanism Description	miR-29b-1 overexpression sensitized 3AB-OS cells to chemotherapeutic drug-induced apoptosis miR-29b-1 negatively regulated the expression of Bcl-2. Overexpression of miR-125b inhibited proliferation, migration, and invasion of OS cells and reduced the chemotherapy resistance of OS cells to cisplatin by targeting Bcl-2.
Key Molecule: Protein sprouty homolog 2 (SPRY2)				[32]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
	HLNG cells	Bone marrow	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	Northern blotting
Experiment for Drug Resistance	Scratch assay
Mechanism Description	miR-21 regulatory network plays a role in tumorigenesis of osteosarcoma. Its expression facilitates cell proliferation and decreases cellular sensitivity towards cisplatin. Both effects can be rescued by Spry2, a target protein downregulated by increased miR-21 levels.
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2)				[33]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	miR138/EZH2 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
Experiment for Molecule Alteration	Western blot analysis; Flow cytometric assay
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-138 acts as a tumor suppressor in osteosarcoma, inhibiting cell proliferation, migration, and invasion by downregulating EZH2 expression. Mir-138 overexpression also enhances osteosarcoma cell chemosensitivity to cisplatin by targeting EZH2.
Key Molecule: Homeodomain-interacting protein kinase 3 (HIPK3)				[35]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.
Key Molecule: Krueppel-like factor 12 (KLF12)				[35]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.
Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51)				[37], [38]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Survival assay/crystal violet staining assay
Mechanism Description	miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization. And overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.
Key Molecule: DNA repair protein RAD51 homolog 4 (RAD51D)				[37]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Survival assay/crystal violet staining assay
Mechanism Description	miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.
Key Molecule: DNA repair protein REV1 (REV1)				[38]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	Overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Decitabine

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Cyclin-dependent kinase inhibitor 2A (CDKN2A)				[39]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Decitabine			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
	HOTAIR-miR126-DNMT1-CDkN2A axis		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
	NHOst cells	Bone	Homo sapiens (Human)	N.A.
	HFob 1.19	Bone	Homo sapiens (Human)	CVCL_3708
Experiment for Molecule Alteration	RT-qPCR; ChIP assay
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	HOTAIR represses the expression of CDkN2A through inhibiting the promoter activity of CDkN2A by RNA hypermethylation. HOTAIR depletion increases the sensibility of OS cells to DNMT1 inhibitor through regulating the viability and apoptosis of OS cells via HOTAIR-miR126-DNMT1-CDkN2A axis.
Key Molecule: HOX transcript antisense RNA (HOTAIR)				[39]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Decitabine			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
	HOTAIR-miR126-DNMT1-CDkN2A axis		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
	NHOst cells	Bone	Homo sapiens (Human)	N.A.
	HFob 1.19	Bone	Homo sapiens (Human)	CVCL_3708
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	HOTAIR represses the expression of CDkN2A through inhibiting the promoter activity of CDkN2A by RNA hypermethylation. HOTAIR depletion increases the sensibility of OS cells to DNMT1 inhibitor through regulating the viability and apoptosis of OS cells via HOTAIR-miR126-DNMT1-CDkN2A axis.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1)				[39]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Decitabine			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
	HOTAIR-miR126-DNMT1-CDkN2A axis		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
	NHOst cells	Bone	Homo sapiens (Human)	N.A.
	HFob 1.19	Bone	Homo sapiens (Human)	CVCL_3708
Experiment for Molecule Alteration	RT-qPCR; Western blot analysis; ChIP assay
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	HOTAIR activates the expression of DNMT1 through repressing miR126, which is the negative regulator of DNMT1. HOTAIR depletion increases the sensibility of OS cells to DNMT1 inhibitor through regulating the viability and apoptosis of OS cells via HOTAIR-miR126-DNMT1-CDkN2A axis.

Doxorubicin

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-152				[41]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
	c-Met/PI3K/AKT signaling pathway		Activation	hsa01521
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay; Soft agar assay
Mechanism Description	LncRNAPVT1 targets miR-152 to enhance chemoresistance of osteosarcoma to doxorubicin through activating c-MET/PI3k/AkT pathway.
Key Molecule: Pvt1 oncogene (PVT1)				[41]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
	c-Met/PI3K/AKT signaling pathway		Activation	hsa01521
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay; Soft agar assay
Mechanism Description	LncRNAPVT1 targets miR-152 to enhance chemoresistance of osteosarcoma to doxorubicin through activating c-MET/PI3k/AkT pathway.
Key Molecule: hsa-miR-34a-5p				[3], [7]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ATF2/ATF3/ATF4 signaling pathway		Inhibition	hsa04915
In Vitro Model	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Annexin V-FITC/propidium iodide (PI) staining assay
Mechanism Description	The miR34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene. And miR34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene.
Key Molecule: hsa-miR-20a-5p				[42]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	miR20a-5p modulates multi-drug resistance by repressing SDC2 expression in OS cells.
Key Molecule: hsa-mir-375				[43]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	Multivariate analysis of overall survival or disease-free survival assay
Mechanism Description	miR375 overexpression could increase the cisplatin sensitivity of human gastric cancer cells by regulating ERBB2.
Key Molecule: hsa-miR-3182				[44]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	ODRUL/miR3182/MMP2 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Dual Luciferase Reporter Assay; PCR
Experiment for Drug Resistance	Wound Healing Assay; Colony Formation Assay; CCK8 Assay
Mechanism Description	LncRNA ODRUL Contributes to Osteosarcoma Progression through the miR3182/MMP2 Axis. miR3182 expression and function are inversely correlated with ODRUL expression in vitro and in vivo, miR3182 negatively regulated the mRNA level and the protein level of MMP2 expression. ODRUL could directly interact with miR3182 and upregulate MMP2 expression via its competing endogenous RNA activity on miR3182 at the posttranscriptional level.
Key Molecule: FOXC2 antisense RNA 1 (FOXC2-AS1)				[44]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	ODRUL/miR3182/MMP2 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	PCR
Experiment for Drug Resistance	Wound Healing Assay; Colony Formation Assay; CCK8 Assay
Mechanism Description	LncRNA ODRUL Contributes to Osteosarcoma Progression through the miR3182/MMP2 Axis. miR3182 expression and function are inversely correlated with ODRUL expression in vitro and in vivo, miR3182 negatively regulated the mRNA level and the protein level of MMP2 expression. ODRUL could directly interact with miR3182 and upregulate MMP2 expression via its competing endogenous RNA activity on miR3182 at the posttranscriptional level.
Key Molecule: hsa-miR-140-5p				[45]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell autophagy		Activation	hsa04140
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	hFOB1.19 cells	Fetal bone	Homo sapiens (Human)	CVCL_3708
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	IC50 assay; Flow cytometric analysis
Mechanism Description	miR140-5p/HMGN5/autophagy regulatory loop plays a critical role in chemoresistance in osteosarcoma, miR 140-5p regulates osteosarcoma chemoresistance by targeting HMGN5 and autophagy.
Key Molecule: FOXC2 antisense RNA 1 (FOXC2-AS1)				[46]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Colony formation assay
Mechanism Description	Antisense LncRNA FOXC2-AS1 promotes doxorubicin resistance in osteosarcoma by increasing the expression of FOXC2. FOXC2-AS1 contributes to doxorubicin resistance by increasing FOXC2 and further facilitating ABCB1.
Key Molecule: Delta-like protein 1 (DLL1)				[7]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ATF2/ATF3/ATF4 signaling pathway		Inhibition	hsa04915
In Vitro Model	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
	MG63.2 cells	Bone	Homo sapiens (Human)	CVCL_R705
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	IC50 assay; Flow cytometric analysis
Mechanism Description	miR34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene. The activity of the ATF2/ATF3/ATF4 pathway was reduced in the miR34a-5p mimic-transfected G-292 cells but increased in the miR34a-5p antagomiRtransfected SJSA-1 cells, hence the ATF2/ATF3/ATF4 pathway was validated to be involved in the OS chemoresistance mediated by miR34a-5p.
Key Molecule: Small nucleolar RNA host gene 12 (SNHG12)				[47]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	The up-regulation of MCL1 reversed the sensitivity of doxorubicin induced by miR-320a mimics and knockdown of SNHG12.
Key Molecule: hsa-mir-320				[47]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	The up-regulation of MCL1 reversed the sensitivity of doxorubicin induced by miR-320a mimics and knockdown of SNHG12.
Key Molecule: hsa-miR-199a-3p				[4]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	NF-kappaB signaling pathway		Inhibition	hsa04064
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The Ak4 gene is one of the targets of miR-199a-3p and negatively correlates with the effect of miR-199a-3p on OS drug-resistance.
Key Molecule: hsa_circ_PVT1				[10]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell colony		Activation	hsa05200
	Cell viability		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	KHOS cells	Bone	Homo sapiens (Human)	CVCL_2546
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Colony formation assay
Mechanism Description	CircPVT1 knockdown reduces the expression of classical multidrug resistance related gene-ABCB1 in OS cells.
Key Molecule: hsa-miR-184				[48]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	AKT/BCL2 signaling pathway		Regulation	N.A.
	Cell apoptosis		Activation	hsa04210
	NF-kappaB signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	microRNA-184 modulates doxorubicin resistance in osteosarcoma cells by targeting BCL2L1 and enhancing the level of it.
Key Molecule: hsa-miR-34a-5p				[5]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	MEF2 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
	MG63.2 cells	Bone	Homo sapiens (Human)	CVCL_R705
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.
Key Molecule: hsa-mir-30a				[49]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Down-regulation of miR-30a contributed to chemoresistance of osteosarcoma cells through regulating autophagy. Furthermore, to investigate the mechanism of miR-130a in regulating autophagy, bioinformatics analysis was performed. The results showed that the 3'-UTR region of Beclin-1 were the binding sites for miR-30a. Consistently, previous studies demonstrated that Beclin-1 was the directly target of miR-30a.
Key Molecule: hsa-miR-146b-5p				[12]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
	Cell viability		Activation	hsa05200
	Wnt/Beta-catenin signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	hFOB1.19 cells	Fetal bone	Homo sapiens (Human)	CVCL_3708
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	miR-146b-5p was highly expressed in human osteosarcoma tissues and an elevated expression of miR-146b-5p was observed in human osteosarcoma tissues after chemotherapy. Furthermore, it was shown that miR-146b-5p overexpression promoted migration and invasiveness. miR-146b-5p overexpression also increased resistance to chemotherapy. Moreover, knockdown of miR-146b-5p substantially inhibited migration and invasion of osteosarcoma cells as well as rendered them significantly more sensitive to chemotherapy. Results of western blot assay indicated that miR-146b-5p increased MMP-16 protein expression and showed a decrease of ZNRF3 protein. Whereas, IWR-1-endo, an inhibitor of Wnt/beta-catenin, suppressed the decrease in apoptosis of osteosarcoma cells caused by miR-146b-5p overexpression. These results indicated that miR-146b-5p promoted proliferation, migration and invasiveness.
Key Molecule: hsa-mir-143				[50]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
In Vivo Model	NOD-SCID IL2-rgamma -null (NSG) mouse engraftment model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay; Matrigel colony formation assay; Hoechst33342 staining assay
Mechanism Description	In chemoresistant SAOS-2 and U2OS osteosarcomas cells, miR-143 levels were significantly downregulated and accompanied by increases in ATG2B, Bcl-2, and/or LC3-II protein levels, high rate of ALDH1+CD133+ cells, and an increase in Matrigel colony formation ability. H2O2 upregulated p53 and miR-143, but downregulated ATG2B, Bcl-2, and LC3-I expression in U2OS cells (wild-type p53) but not in SAOS-2 (p53-null) cells. Forced miR-143 expression significantly reversed chemoresistance as well as downregulation of ATG2B, LC3-I, and Bcl-2 expression in SAOS-2- and U2OS-resistant cells. Forced miR-143 expression significantly inhibited tumor growth in xenograft SAOS-2-Dox and U2OS-Dox animal models. Loss of miR-143 expression is associated with poor prognosis of patients with osteosarcoma underlying chemotherapy. The chemoresistance of osteosarcoma tumor cells to doxorubicin is associated with the downregulation of miR-143 expression, activation of ALDH1+CD133+ cells, activation of autophagy, and inhibition of cell death.
Key Molecule: hsa-mir-155				[51]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	During treatment with Dox or Cis in osteosarcoma cells, miR-155 expression was strongly induced. The increased miR-155 expression facilitated tumor cell proliferation via upregulating autophagy, thus, facilitated the resistance of osteosarcoma cells to Dox or Cis.
Key Molecule: hsa-miR-301a				[52]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	AMPKalpha1/HMGCR		Regulation	N.A.
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	MG-63 cells	Bone	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	In this study, we found that doxorubicin induced time-dependent expression of miR-301a in OS cells. Meantime, doxorubicin promoted HMGCR expression and inhibited AMPKalpha1 expression, which was further facilitated by miR-301a overexpression. Luciferase reporter assay identified AMPKalpha1 as direct target gene of miR-301a. Notably, miR-301a reduced doxorubicin-induced cell apoptosis whereas anti-miR-301a enhanced apoptosis in OS cells, suggesting that up-regulation of miR-301a contributed to chemoresistance of OS cells.
Key Molecule: hsa-miR-203a-3p				[15]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The most upregulated circRNA, miRNA, and mRNA were hsa_circ_0004674 (17-fold change), hsa-miR-337-3p (12-fold change), and C6orf106 (124-fold change), respectively. The most downregulated circRNA, miRNA, and mRNA were hsa_circ_0068458 (12-fold change), hsa-miR-203a-3p (10-fold change), and AKR1C2 (197-fold change), respectively.
Key Molecule: hsa-miR-337-3p				[15]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The most upregulated circRNA, miRNA, and mRNA were hsa_circ_0004674 (17-fold change), hsa-miR-337-3p (12-fold change), and C6orf106 (124-fold change), respectively. The most downregulated circRNA, miRNA, and mRNA were hsa_circ_0068458 (12-fold change), hsa-miR-203a-3p (10-fold change), and AKR1C2 (197-fold change), respectively.
Key Molecule: hsa-miR-202				[53]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	RT-PCR; Luciferase activity assay; Western blot
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	This study aimed to explore miR-202 contributions to drug resistance in osteosarcoma
Key Molecule: hsa-miR-142-5p				[16]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	circ_0004674/miR-142-5p/MCL1 axis		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	KHOS cells	Bone	Homo sapiens (Human)	CVCL_2546
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
In Vivo Model	Osteosarcoma patients; Nude mouse xenograft model			Homo sapiens
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry; Transwell assay; Wound healing assay
Mechanism Description	Moreover, the expression and function of miR-142-5p were conversely correlated with circ_0004674 in vitro. RIP, pull-down, luciferase assay, and RNA FISH demonstrated that circ_0004674 could compete with MCL1 for miR-142-5p binding to counteract miR-142-5p-mediated repression of MCL1 at the post-transcriptional level. To sum up, our study sheds light on the critical role of the oncogenic circ_0004674/miR-142-5p/MCL1 axis in OS progression and chemoresistance, providing a novel potential target for OS therapy.
Key Molecule: hsa-miR-25-3p				[54]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Wnt/beta-catenin pathway		Regulation	N.A.
In Vitro Model	143B cells	Bone	Homo sapiens (Human)	CVCL_2270
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
In Vivo Model	Osteosarcoma patients			Homo sapiens
Experiment for Molecule Alteration	RT-PCR; Western blot; Luciferase assay; Immunohistochemistry
Experiment for Drug Resistance	Cell proliferation assays; Cytotoxicity assays; Cell migration assay; Cell invasion assay
Mechanism Description	Intracellular miR-25-3p contributed to cellular proliferation, invasion, and drug resistance, which are lethal OS phenotypes.By contrast, the expression of the Wnt signaling inhibitor DKK3, a miR-25-3p target, was correlated with a good prognosis in the OS patients.
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1)				[10]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell colony		Activation	hsa05200
	Cell viability		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	KHOS cells	Bone	Homo sapiens (Human)	CVCL_2546
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Colony formation assay
Mechanism Description	CircPVT1 knockdown reduces the expression of classical multidrug resistance related gene-ABCB1 in OS cells.
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)				[55]
Metabolic Type	Glucose metabolism
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vivo Model	Nude mice, with MG-63/Dox cells			Mice
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Tumor volume assay; Tumor weight assay
Mechanism Description	Mechanistic analysis indicated that the mRNA stability, rather than ERRalpha transcription was markedly increased in chemoresistant OS cells. Therefore, it was hypothesized that the 3'-untranslated region of ERRalpha mRNA was methylated by N6-methyladenine, which could further recruit insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to suppress mRNA decay and increase mRNA stability. IGF2BP1 knockdown downregulated ERRalpha and reversed the metabolic alteration of resistant OS cells. Additionally, the oncogenic effect of the IGF2BP1/ERRalpha axis on Dox-resistant OS cells was verified by in vitro and in vivo experiments. Clinical analysis also revealed that the expression levels of IGF2BP1 and ERRalpha were associated with the clinical progression of OS.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Syndecan-2 (SDC2)				[42]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
Experiment for Molecule Alteration	Luciferase reporter assay; Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	miR20a-5p modulates multi-drug resistance by repressing SDC2 expression in OS cells.
Key Molecule: Nucleosome-binding protein 1 (NSBP1)				[45]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell autophagy		Activation	hsa04140
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	hFOB1.19 cells	Fetal bone	Homo sapiens (Human)	CVCL_3708
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Luciferase activity assay; Western blot analysis
Experiment for Drug Resistance	IC50 assay; Flow cytometric analysis
Mechanism Description	miR140-5p/HMGN5/autophagy regulatory loop plays a critical role in chemoresistance in osteosarcoma, miR 140-5p regulates osteosarcoma chemoresistance by targeting HMGN5 and autophagy.
Key Molecule: Forkhead box protein C2 (FOXC2)				[46]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Colony formation assay
Mechanism Description	Antisense LncRNA FOXC2-AS1 promotes doxorubicin resistance in osteosarcoma by increasing the expression of FOXC2. FOXC2-AS1 contributes to doxorubicin resistance by increasing FOXC2 and further facilitating ABCB1.
Key Molecule: Type-1 angiotensin II receptor (AGTR1)				[3]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Annexin V-FITC/propidium iodide (PI) staining assay
Mechanism Description	The miR34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene.
Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)				[47]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	The up-regulation of MCL1 reversed the sensitivity of doxorubicin induced by miR-320a mimics and knockdown of SNHG12.
Key Molecule: Adenylate kinase 4 (AK4)				[4]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	NF-kappaB signaling pathway		Inhibition	hsa04064
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis; RIP assay; Luciferase reporter assay
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The Ak4 gene is one of the targets of miR-199a-3p and negatively correlates with the effect of miR-199a-3p on OS drug-resistance.
Key Molecule: Bcl-2-like protein 11 (BCL2L11)				[48]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	AKT/BCL2 signaling pathway		Regulation	N.A.
	Cell apoptosis		Activation	hsa04210
	NF-kappaB signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	microRNA-184 modulates doxorubicin resistance in osteosarcoma cells by targeting BCL2L1 and enhancing the level of it.
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT)				[5]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	MEF2 signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	G-292 cells	Bone	Homo sapiens (Human)	CVCL_2909
	SJSA-1 cells	Bone	Homo sapiens (Human)	CVCL_1697
	MG63.2 cells	Bone	Homo sapiens (Human)	CVCL_R705
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.
Key Molecule: Beclin-1 (BECN1)				[49]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Down-regulation of miR-30a contributed to chemoresistance of osteosarcoma cells through regulating autophagy. Furthermore, to investigate the mechanism of miR-130a in regulating autophagy, bioinformatics analysis was performed. The results showed that the 3'-UTR region of Beclin-1 were the binding sites for miR-30a. Consistently, previous studies demonstrated that Beclin-1 was the directly target of miR-30a.
Key Molecule: E3 ubiquitin-protein ligase ZNRF3 (ZNRF3)				[12]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	Wnt/Beta-catenin signaling pathway		Regulation	N.A.
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	hFOB1.19 cells	Fetal bone	Homo sapiens (Human)	CVCL_3708
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	miR-146b-5p was highly expressed in human osteosarcoma tissues and an elevated expression of miR-146b-5p was observed in human osteosarcoma tissues after chemotherapy. Furthermore, it was shown that miR-146b-5p overexpression promoted migration and invasiveness. miR-146b-5p overexpression also increased resistance to chemotherapy. Moreover, knockdown of miR-146b-5p substantially inhibited migration and invasion of osteosarcoma cells as well as rendered them significantly more sensitive to chemotherapy. Results of western blot assay indicated that miR-146b-5p increased MMP-16 protein expression and showed a decrease of ZNRF3 protein. Whereas, IWR-1-endo, an inhibitor of Wnt/beta-catenin, suppressed the decrease in apoptosis of osteosarcoma cells caused by miR-146b-5p overexpression. These results indicated that miR-146b-5p promoted proliferation, migration and invasiveness.
Key Molecule: Autophagy-related protein 2 homolog B (ATG2B)				[50]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Matrigel colony formation assay; Hoechst33342 staining assay
Mechanism Description	In chemoresistant SAOS-2 and U2OS osteosarcomas cells, miR-143 levels were significantly downregulated and accompanied by increases in ATG2B, Bcl-2, and/or LC3-II protein levels, high rate of ALDH1+CD133+ cells, and an increase in Matrigel colony formation ability. H2O2 upregulated p53 and miR-143, but downregulated ATG2B, Bcl-2, and LC3-I expression in U2OS cells (wild-type p53) but not in SAOS-2 (p53-null) cells. Forced miR-143 expression significantly reversed chemoresistance as well as downregulation of ATG2B, LC3-I, and Bcl-2 expression in SAOS-2- and U2OS-resistant cells. Forced miR-143 expression significantly inhibited tumor growth in xenograft SAOS-2-Dox and U2OS-Dox animal models. Loss of miR-143 expression is associated with poor prognosis of patients with osteosarcoma underlying chemotherapy. The chemoresistance of osteosarcoma tumor cells to doxorubicin is associated with the downregulation of miR-143 expression, activation of ALDH1+CD133+ cells, activation of autophagy, and inhibition of cell death.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[50]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Matrigel colony formation assay; Hoechst33342 staining assay
Mechanism Description	In chemoresistant SAOS-2 and U2OS osteosarcomas cells, miR-143 levels were significantly downregulated and accompanied by increases in ATG2B, Bcl-2, and/or LC3-II protein levels, high rate of ALDH1+CD133+ cells, and an increase in Matrigel colony formation ability. H2O2 upregulated p53 and miR-143, but downregulated ATG2B, Bcl-2, and LC3-I expression in U2OS cells (wild-type p53) but not in SAOS-2 (p53-null) cells. Forced miR-143 expression significantly reversed chemoresistance as well as downregulation of ATG2B, LC3-I, and Bcl-2 expression in SAOS-2- and U2OS-resistant cells. Forced miR-143 expression significantly inhibited tumor growth in xenograft SAOS-2-Dox and U2OS-Dox animal models. Loss of miR-143 expression is associated with poor prognosis of patients with osteosarcoma underlying chemotherapy. The chemoresistance of osteosarcoma tumor cells to doxorubicin is associated with the downregulation of miR-143 expression, activation of ALDH1+CD133+ cells, activation of autophagy, and inhibition of cell death.
Key Molecule: Microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A)				[50]
Resistant Disease	Osteosarcoma [ICD-11: 2B51.0]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Matrigel colony formation assay; Hoechst33342 staining assay
Mechanism Description	In chemoresistant SAOS-2 and U2OS osteosarcomas cells, miR-143 levels were significantly downregulated and accompanied by increases in ATG2B, Bcl-2, and/or LC3-II protein levels, high rate of ALDH1+CD133+ cells, and an increase in Matrigel colony formation ability. H2O2 upregulated p53 and miR-143, but downregulated ATG2B, Bcl-2, and LC3-I expression in U2OS cells (wild-type p53) but not in SAOS-2 (p53-null) cells. Forced miR-143 expression significantly reversed chemoresistance as well as downregulation of ATG2B, LC3-I, and Bcl-2 expression in SAOS-2- and U2OS-resistant cells. Forced miR-143 expression significantly inhibited tumor growth in xenograft SAOS-2-Dox and U2OS-Dox animal models. Loss of miR-143 expression is associated with poor prognosis of patients with osteosarcoma underlying chemotherapy. The chemoresistance of osteosarcoma tumor cells to doxorubicin is associated with the downregulation of miR-143 expression, activation of ALDH1+CD133+ cells, activation of autophagy, and inhibition of cell death.

Drug Sensitive Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-320a				[15]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	MG-63 cells	Bone	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	HFOB cells	Bone	Homo sapiens (Human)	CVCL_3708
In Vivo Model	Osteosarcoma patients			Homo sapiens
Experiment for Molecule Alteration	qRT-PCR; Dual luciferase reporter assay; RNA immunoprecipitation (RIP) assay; Western blot
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	Moreover, dual luciferase reporter and RNA immunoprecipitation assays revealed that miR-320a targeted to SNHG12. Besides, knockdown of SNHG12 contributed to the upregulation of miR-320a and improved the sensitivity of doxorubicin. Additionally, miR-320a inhibited the expression of Myeloid cell leukemia 1 (MCL1). Finally, the results indicated that SNHG12 mediated doxorubicin resistance of osteosarcoma via miR-320a/MCL1 axis.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR)				[56]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qPCR; Microarray assay
Experiment for Drug Resistance	CCK8 assay; Flow cytometric analysis
Mechanism Description	LncRNA FENDRR sensitizes doxorubicin-resistance of osteosarcoma cells through down-regulating ABCB1 and ABCC1.
Key Molecule: hsa-mir-100				[57]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell growth		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay; CCK8 assay
Mechanism Description	Either ZNRF2 overexpression or miR100 depletion increased in vitro OS cell growth and improved cell survival at the presence of Doxorubicin. miR100 bindS to the 3'-UTR of ZNRF2 mRNA to prevent its protein translation, re-expression of miR100 may inhibit OS cell growth and decrease OS cell chemo-resistance.
Key Molecule: Phosphate cytidylyltransferase 1A, choline (PCYT1A)				[58]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	TUNEL Assay; MTT assay; Flow cytometric analysis
Mechanism Description	LncRNA CTA-miR210 axis plays an important role in reducing OS chemoresistance. LncRNA CTA could be activated by doxorubicin (DOX), and could promote OS cell apoptosis by competitively binding miR210, while inhibit cell autophagy.
Key Molecule: hsa-mir-210				[58]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR; Dual luciferase reporter assay
Experiment for Drug Resistance	TUNEL Assay; MTT assay; Flow cytometric analysis
Mechanism Description	LncRNA CTA-miR210 axis plays an important role in reducing OS chemoresistance. LncRNA CTA could be activated by doxorubicin (DOX), and could promote OS cell apoptosis by competitively binding miR210, while inhibit cell autophagy.
Key Molecule: hsa-mir-410				[24]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HFob 1.19	Bone	Homo sapiens (Human)	CVCL_3708
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	microRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma, miR410 directly decreased ATG16L1 expression by targeting its 3'-untranslated region.
Key Molecule: hsa-mir-124				[59]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	ZR75-1 cells	Breast	Homo sapiens (Human)	CVCL_0588
	HCC1937 cells	Breast	Homo sapiens (Human)	CVCL_0290
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-124 may be involved in DNA repair by directly targeting ATMIN and PARP1, suggesting that multiple DNA repair pathways are affected by miR-124 and therefore manipulation of miR-124 level/activity may improve the efficacy of chemotherapies that induce DNA damage. repression of ATMIN (+) the HR repair defect induced by miR-124, and restoration of ATMIN reversed the effect of miR-124 overexpression in breast cancer cells. Therefore, it is intriguing to further speculate which of the multiple roles of ATMIN is specifically affected in breast carcinogenesis. On the other hand, PARP1-mediated processes play a role in oncogenesis, cancer progression, and therapeutic resistance.
Key Molecule: hsa-miR-199a-3p				[60]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	KHOS cells	Bone	Homo sapiens (Human)	CVCL_2546
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	CD44 was overexpressed in metastatic and recurrent osteosarcoma as compared with primary tumors. Higher expression of CD44 was found in both patients with shorter survival and patients who exhibited unfavorable response to chemotherapy before surgical resection. Additionally, the 3'-untranslated region of CD44 mRNA was the direct target of microRNA-199a-3p (miR-199a-3p). Overexpression of miR-199a-3p significantly inhibited CD44 expression in osteosarcoma cells. miR-199a-3p is One of the most dramatically decreased miRs in osteosarcoma cells and tumor tissues as compared with normal osteoblast cells. Transfection of miR-199a-3p significantly increased the drug sensitivity through down-regulation of CD44 in osteosarcoma cells. Taken together, these results suggest that the CD44-miR-199a-3p axis plays an important role in the development of metastasis, recurrence, and drug resistance of osteosarcoma. Developing strategies to target CD44 may improve the clinical outcome of osteosarcoma.
Key Molecule: hsa-mir-382				[35]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.
Key Molecule: hsa-mir-101				[61]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	Quantitative GFP-LC3 analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	The miR-101 not only decreases the formation of autophagic vesicles but also reduces the expression of LC-3II and Atg 4. This part of the study shows that miR-101 blocks chemotherapy-induced autophagy in OS cells. The sensitivity of OS cells to chemotherapy is increased by miR-101 blocked autophagy. miR-101 blocked the chemotherapy induced autophagy, and the blocked autophagy by miR-101 enhances the sensitivity of the OS cell line U-2 in vitro.
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1)				[56]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Flow cytometric analysis
Mechanism Description	LncRNA FENDRR sensitizes doxorubicin-resistance of osteosarcoma cells through down-regulating ABCB1 and ABCC1.
Key Molecule: Multidrug resistance-associated protein 1 (MRP1)				[56]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	SAOS-2 cells	Bone marrow	Homo sapiens (Human)	CVCL_0548
	HOS cells	Bone	Homo sapiens (Human)	CVCL_0312
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Flow cytometric analysis
Mechanism Description	LncRNA FENDRR sensitizes doxorubicin-resistance of osteosarcoma cells through down-regulating ABCB1 and ABCC1.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: E3 ubiquitin-protein ligase ZNRF2 (ZNRF2)				[57]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell growth		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
Experiment for Molecule Alteration	Western blot analysis; Luciferase reporter assay
Experiment for Drug Resistance	MTT assay; CCK8 assay
Mechanism Description	Either ZNRF2 overexpression or miR100 depletion increased in vitro OS cell growth and improved cell survival at the presence of Doxorubicin. miR100 bindS to the 3'-UTR of ZNRF2 mRNA to prevent its protein translation, re-expression of miR100 may inhibit OS cell growth and decrease OS cell chemo-resistance.
Key Molecule: Autophagy-related protein 16-1 (ATG16L1)				[24]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	HFob 1.19	Bone	Homo sapiens (Human)	CVCL_3708
Experiment for Molecule Alteration	Luciferase reporter assay; Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	microRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma, miR410 directly decreased ATG16L1 expression by targeting its 3'-untranslated region.
Key Molecule: ATM interactor (ATMIN)				[59]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	ZR75-1 cells	Breast	Homo sapiens (Human)	CVCL_0588
	HCC1937 cells	Breast	Homo sapiens (Human)	CVCL_0290
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-124 may be involved in DNA repair by directly targeting ATMIN and PARP1, suggesting that multiple DNA repair pathways are affected by miR-124 and therefore manipulation of miR-124 level/activity may improve the efficacy of chemotherapies that induce DNA damage. repression of ATMIN (+) the HR repair defect induced by miR-124, and restoration of ATMIN reversed the effect of miR-124 overexpression in breast cancer cells. Therefore, it is intriguing to further speculate which of the multiple roles of ATMIN is specifically affected in breast carcinogenesis. On the other hand, PARP1-mediated processes play a role in oncogenesis, cancer progression, and therapeutic resistance.
Key Molecule: Poly[ADP-ribose] synthase 1 (PARP1)				[59]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	ZR75-1 cells	Breast	Homo sapiens (Human)	CVCL_0588
	HCC1937 cells	Breast	Homo sapiens (Human)	CVCL_0290
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-124 may be involved in DNA repair by directly targeting ATMIN and PARP1, suggesting that multiple DNA repair pathways are affected by miR-124 and therefore manipulation of miR-124 level/activity may improve the efficacy of chemotherapies that induce DNA damage. repression of ATMIN (+) the HR repair defect induced by miR-124, and restoration of ATMIN reversed the effect of miR-124 overexpression in breast cancer cells. Therefore, it is intriguing to further speculate which of the multiple roles of ATMIN is specifically affected in breast carcinogenesis. On the other hand, PARP1-mediated processes play a role in oncogenesis, cancer progression, and therapeutic resistance.
Key Molecule: Extracellular matrix receptor III (CD44)				[60]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	KHOS cells	Bone	Homo sapiens (Human)	CVCL_2546
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	CD44 was overexpressed in metastatic and recurrent osteosarcoma as compared with primary tumors. Higher expression of CD44 was found in both patients with shorter survival and patients who exhibited unfavorable response to chemotherapy before surgical resection. Additionally, the 3'-untranslated region of CD44 mRNA was the direct target of microRNA-199a-3p (miR-199a-3p). Overexpression of miR-199a-3p significantly inhibited CD44 expression in osteosarcoma cells. miR-199a-3p is One of the most dramatically decreased miRs in osteosarcoma cells and tumor tissues as compared with normal osteoblast cells. Transfection of miR-199a-3p significantly increased the drug sensitivity through down-regulation of CD44 in osteosarcoma cells. Taken together, these results suggest that the CD44-miR-199a-3p axis plays an important role in the development of metastasis, recurrence, and drug resistance of osteosarcoma. Developing strategies to target CD44 may improve the clinical outcome of osteosarcoma.
Key Molecule: Homeodomain-interacting protein kinase 3 (HIPK3)				[35]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.
Key Molecule: Krueppel-like factor 12 (KLF12)				[35]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MG63 cells	Bone marrow	Homo sapiens (Human)	CVCL_0426
	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
	MNNG/HOS cells	Bone	Homo sapiens (Human)	CVCL_0439
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.
Key Molecule: Ubiquitin-like modifier-activating enzyme Atg 4 (ATG4)				[61]
Sensitive Disease	Osteosarcoma [ICD-11: 2B51.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	U2OS cells	Bone	Homo sapiens (Human)	CVCL_0042
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	The miR-101 not only decreases the formation of autophagic vesicles but also reduces the expression of LC-3II and Atg 4. This part of the study shows that miR-101 blocks chemotherapy-induced autophagy in OS cells. The sensitivity of OS cells to chemotherapy is increased by miR-101 blocked autophagy. miR-101 blocked the chemotherapy induced autophagy, and the blocked autophagy by miR-101 enhances the sensitivity of the OS cell line U-2 in vitro.

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Prof. Feng ZHU (zhufeng@zju.edu.cn)