Molecule Information

General Information of the Molecule (ID: Mol00181)

• Name: Metalloproteinase inhibitor 3 (TIMP3) ,Homo sapiens
• Synonyms: Protein MIG-5; Tissue inhibitor of metalloproteinases 3; TIMP-3
• Molecule Type: Protein
• Gene Name: TIMP3
• Gene ID: 7078
• Location: chr22:32801705-32863041[+]
• Sequence:
  MTPWLGLIVLLGSWSLGDWGAEACTCSPSHPQDAFCNSDIVIRAKVVGKKLVKEGPFGTL
  VYTIKQMKMYRGFTKMPHVQYIHTEASESLCGLKLEVNKYQYLLTGRVYDGKMYTGLCNF
  VERWDQLTLSQRKGLNYRYHLGCNCKIKSCYYLPCFVTSKNECLWTDMLSNFGYPGYQSK
  HYACIRQKGGYCSWYRGWAPPDKSIINATDP
• Function: Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. May form part of a tissue-specific acute response to remodeling stimuli. Known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, MMP-14 and MMP-15.
• Uniprot ID: TIMP3_HUMAN
• Ensembl ID: ENSG00000100234
• HGNC ID: HGNC:11822

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 7 drug(s) in total

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Cervical cancer [1]

• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Colony formation assay
• Mechanism Description: Down-regulation of LncRNA GAS5 can suppress TIMP3 and PDCD4 expression by enhancing miR-21 expression to suppress apoptosis and promote migration, invasion and cisplatin resistance in cervical cancer through the STAT3 signaling pathway.

Dovitinib lactate

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Renal carcinoma [2]

• Sensitive Disease: Renal carcinoma [ICD-11: 2C90.2]
• Sensitive Drug: Dovitinib lactate
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: RCC10 cells; Kidney; Homo sapiens (Human); CVCL_6265
• In Vitro Model: RCC4 cells; Kidney; Homo sapiens (Human); CVCL_0498
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Celltiter96 Aqueous Non Radioactive Cell Proliferation Assay
• Mechanism Description: Tumor suppressor genes like PTEN, PDCD4 and TIMP3, are target genes of miR21. PTEN is a potent inhibitor of PI3k/Akt pathway, as well as a direct target of miR21.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hepatocellular carcinoma [3]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TIMP3 is a tumor suppressor and a validated miR-181 target. Ectopic expression and depletion of miR-181b showed that miR-181b enhanced MMP2 and MMP9 activity and promoted growth, clonogenic survival, migration and invasion of HCC cells that could be reversed by modulating TIMP3 level.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Oral squamous cell carcinoma [4]

• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Annexin V-fluorescein isothiocyanate (FITC)/Hoechst double staining; MTT assay
• Mechanism Description: OSCC cells are resistant to doxorubicin through upregulation of miR221, which in turn downregulates TIMP3.

Disease Class: Gastric cancer [5]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Suppression of miR-21-5p expression sensitizes SGC7901/DOX cells to DOX via upregulating PTEN and TIMP3.

Fluorouracil

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Renal carcinoma [2]

• Sensitive Disease: Renal carcinoma [ICD-11: 2C90.2]
• Sensitive Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: RCC10 cells; Kidney; Homo sapiens (Human); CVCL_6265
• In Vitro Model: RCC4 cells; Kidney; Homo sapiens (Human); CVCL_0498
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Celltiter96 Aqueous Non Radioactive Cell Proliferation Assay
• Mechanism Description: Tumor suppressor genes like PTEN, PDCD4 and TIMP3, are target genes of miR21. PTEN is a potent inhibitor of PI3k/Akt pathway, as well as a direct target of miR21.

Oxaliplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Renal carcinoma [2]

• Sensitive Disease: Renal carcinoma [ICD-11: 2C90.2]
• Sensitive Drug: Oxaliplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: RCC10 cells; Kidney; Homo sapiens (Human); CVCL_6265
• In Vitro Model: RCC4 cells; Kidney; Homo sapiens (Human); CVCL_0498
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Celltiter96 Aqueous Non Radioactive Cell Proliferation Assay
• Mechanism Description: Tumor suppressor genes like PTEN, PDCD4 and TIMP3, are target genes of miR21. PTEN is a potent inhibitor of PI3k/Akt pathway, as well as a direct target of miR21.

Paclitaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Renal carcinoma [2]

• Sensitive Disease: Renal carcinoma [ICD-11: 2C90.2]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: RCC10 cells; Kidney; Homo sapiens (Human); CVCL_6265
• In Vitro Model: RCC4 cells; Kidney; Homo sapiens (Human); CVCL_0498
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Celltiter96 Aqueous Non Radioactive Cell Proliferation Assay
• Mechanism Description: Tumor suppressor genes like PTEN, PDCD4 and TIMP3, are target genes of miR21. PTEN is a potent inhibitor of PI3k/Akt pathway, as well as a direct target of miR21.

Tamoxifen

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [6]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Tamoxifen
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-8 assay
• Mechanism Description: Transfection of AS-miR-221 and AS-miR-222 dramatically inhibited expression of miR-221 and miR-222, respectively, in both MCF-7 and MDA-MB-231 cells (P<0.05-0.01). Down-regulation of miR-221/222 significantly increased the expression of TIMP3 compared with controls (P<0.05-0.01). The viability of estrogen receptor (ER)-positive MCF-7 cells transfected with AS-miR-221 or/and AS-miR-222 was significantly reduced by tamoxifen (P<0.05-0.01). Suppression of miRNA-221/222 increases the sensitivity of ER-positive MCF-7 breast cancer cells to tamoxifen. This effect is mediated through upregulation of TIMP3. These findings suggest that upregulation of TIMP3 via inhibition of miRNA-221/222 could be a promising therapeutic approach for breast cancer.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Oral squamous cell carcinoma [ICD-11: 2B6E]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Oral tissue
• The Specified Disease: Oral squamous cell carcinoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.62E-01; Fold-change: -2.10E-01; Z-score: -1.93E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.10E-16; Fold-change: 7.87E-01; Z-score: 1.38E+00

Gastric cancer [ICD-11: 2B72]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Gastric tissue
• The Specified Disease: Gastric cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.59E-01; Fold-change: 1.51E-01; Z-score: 9.60E-02
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.55E-04; Fold-change: 5.85E-01; Z-score: 1.11E+00

Liver cancer [ICD-11: 2C12]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Liver
• The Specified Disease: Liver cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.64E-01; Fold-change: 2.56E-01; Z-score: 4.24E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 5.21E-08; Fold-change: 3.37E-01; Z-score: 5.53E-01
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 7.19E-01; Fold-change: 1.01E-01; Z-score: 2.30E-01

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.55E-07; Fold-change: -3.43E-01; Z-score: -3.64E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.24E-03; Fold-change: -3.17E-01; Z-score: -3.86E-01

Cervical cancer [ICD-11: 2C77]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Cervix uteri
• The Specified Disease: Cervical cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.25E-04; Fold-change: 3.28E-01; Z-score: 7.48E-01

Kidney cancer [ICD-11: 2C90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Kidney
• The Specified Disease: Kidney cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.26E-01; Fold-change: -4.20E-01; Z-score: -5.87E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 8.28E-07; Fold-change: -3.22E-01; Z-score: -5.62E-01

References

• Ref 1: Growth arrest-specific 5 attenuates cisplatin-induced apoptosis in cervical cancer by regulating STAT3 signaling via miR-21. J Cell Physiol. 2019 Jun;234(6):9605-9615. doi: 10.1002/jcp.27647. Epub 2018 Oct 23.
• Ref 2: Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma. Tumour Biol. 2017 Jul;39(7):1010428317707372. doi: 10.1177/1010428317707372.
• Ref 3: TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene. 2010 Mar 25;29(12):1787-97. doi: 10.1038/onc.2009.468. Epub 2009 Dec 21.
• Ref 4: Oral squamous cell carcinoma cells are resistant to doxorubicin through upregulation of miR 221. Mol Med Rep. 2017 Sep;16(3):2659-2667. doi: 10.3892/mmr.2017.6915. Epub 2017 Jul 4.
• Ref 5: miR 21 5p confers doxorubicin resistance in gastric cancer cells by targeting PTEN and TIMP3. Int J Mol Med. 2018 Apr;41(4):1855-1866. doi: 10.3892/ijmm.2018.3405. Epub 2018 Jan 18.
• Ref 6: Downregulation of miR-221/222 enhances sensitivity of breast cancer cells to tamoxifen through upregulation of TIMP3. Cancer Gene Ther. 2014 Jul;21(7):290-6. doi: 10.1038/cgt.2014.29. Epub 2014 Jun 13.