Molecule Information

General Information of the Molecule (ID: Mol00164)

• Name: Mothers against decapentaplegic homolog 4 (SMAD4) ,Homo sapiens
• Synonyms: MAD homolog 4; Mothers against DPP homolog 4; Deletion target in pancreatic carcinoma 4; SMAD family member 4; SMAD 4; Smad4; hSMAD4; DPC4; MADH4
• Molecule Type: Protein
• Gene Name: SMAD4
• Gene ID: 4089
• Location: chr18:51028394-51085045[+]
• Sequence:
  MDNMSITNTPTSNDACLSIVHSLMCHRQGGESETFAKRAIESLVKKLKEKKDELDSLITA
  ITTNGAHPSKCVTIQRTLDGRLQVAGRKGFPHVIYARLWRWPDLHKNELKHVKYCQYAFD
  LKCDSVCVNPYHYERVVSPGIDLSGLTLQSNAPSSMMVKDEYVHDFEGQPSLSTEGHSIQ
  TIQHPPSNRASTETYSTPALLAPSESNATSTANFPNIPVASTSQPASILGGSHSEGLLQI
  ASGPQPGQQQNGFTGQPATYHHNSTTTWTGSRTAPYTPNLPHHQNGHLQHHPPMPPHPGH
  YWPVHNELAFQPPISNHPAPEYWCSIAYFEMDVQVGETFKVPSSCPIVTVDGYVDPSGGD
  RFCLGQLSNVHRTEAIERARLHIGKGVQLECKGEGDVWVRCLSDHAVFVQSYYLDREAGR
  APGDAVHKIYPSAYIKVFDLRQCHRQMQQQAATAQAAAAAQAAAVAGNIPGPGSVGGIAP
  AISLSAAAGIGVDDLRRLCILRMSFVKGWGPDYPRQSIKETPCWIEIHLHRALQLLDEVL
  HTMPIADPQPLD
• Function: In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions. Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.
• Uniprot ID: SMAD4_HUMAN
• Ensembl ID: ENSG00000141646
• HGNC ID: HGNC:6770

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

Type(s) of Resistant Mechanism of This Molecule

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 6 drug(s) in total

Bromocriptine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Prolactinomas [1]

• Resistant Disease: Prolactinomas [ICD-11: 2F37.2]
• Resistant Drug: Bromocriptine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: TGF-beta 1/Smad3 pathway; Activation; hsa04350
• In Vitro Model: HS27 cells; Bone; Homo sapiens (Human); CVCL_0E34
• In Vitro Model: MMQ cells; Pituitary gland; Rattus norvegicus (Rat); CVCL_2117
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: TGF-beta1 promotes the synthesis and secretion of collagen fibers in fibroblasts and that the TGF-beta1/Smad3 pathway is involved in the mechanism of prolactinoma resistance by increasing fibrosis through interactions with fibroblasts.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [2]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant 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 proliferation; Activation; hsa05200
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vitro Model: SkOV-3/DDP cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: PVT1 was overexpressed in tumor tissues of cisplatin-resistant patients comparing to cisplatin-sensitive patients. PVT1 knockdown significantly lowered cell viability and increased the percentage of apoptotic tumor cells in SkOV-3/DDP and A2780/DDP cells transfected with siPVT1 and treated with cisplatin. It manifested PVT1 knockdown can reverses the cisplatin resistance in cisplatin-resistant cell lines.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [3]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MCF-7/ADR cells; Breast; Homo sapiens (Human); CVCL_1452
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-574 enhances doxorubicin resistance through down-regulating SMAD4 in breast cancer cells.

Gemcitabine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Pancreatic cancer [4]

• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Sensitive Drug: Gemcitabine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• Cell Pathway Regulation: TGF-beta signaling pathway; Inhibition; hsa04350
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: Su.86.86 cells; Pancreas; Homo sapiens (Human); CVCL_3881
• In Vitro Model: CFPAC1 cells; Pancreas; Homo sapiens (Human); CVCL_1119
• In Vitro Model: KMP3 cells; Pancreas; Homo sapiens (Human); CVCL_8491
• In Vitro Model: KP4-4 cells; Pancreas; Homo sapiens (Human); CVCL_Y142
• In Vitro Model: Panc1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-8 assay; Crystal violet staining assay
• Mechanism Description: Overexpression of miR509-5p and miR1243 increased the expression of E-cadherin through the suppression of EMT-related gene expression and that drug sensitivity increased with a combination of each of these miRNAs and gemcitabine. miR1243 directly regulated SMAD2 and SMAD4, which regulate the TGF-beta signaling pathway, resulting in an induction of the MET phenotype. Suppressing SMADs reduced the effect of TGF-beta.

IFN-alpha

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hepatocellular carcinoma [5]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Resistant Drug: IFN-alpha
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt/Beta signaling pathway; Activation; hsa04310
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-146a confers resistance to IFN-alpha in HCC cells by inhibiting apoptosis through SMAD4.

Oxaliplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colon cancer [6]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Resistant Drug: Oxaliplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Annexin V-PE and 7-AAD double staining method to examine cell viabilityNA; CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Colon cancer [ICD-11: 2B90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Colon
• The Specified Disease: Colon cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.42E-04; Fold-change: -4.09E-01; Z-score: -9.72E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.08E-07; Fold-change: -4.59E-01; Z-score: -6.36E-01

Pancreatic cancer [ICD-11: 2C10]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Pancreas
• The Specified Disease: Pancreatic cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.97E-01; Fold-change: 7.12E-01; Z-score: 8.66E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.99E-04; Fold-change: -3.10E-01; Z-score: -5.12E-01

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: 6.71E-02; Fold-change: 1.14E-01; Z-score: 1.60E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.67E-03; Fold-change: -4.53E-01; Z-score: -5.29E-01
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 4.53E-01; Fold-change: -3.38E-01; Z-score: -4.31E-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: 1.35E-27; Fold-change: 7.60E-01; Z-score: 1.10E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.71E-04; Fold-change: 4.97E-01; Z-score: 5.62E-01

Ovarian cancer [ICD-11: 2C73]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Ovary
• The Specified Disease: Ovarian cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.19E-03; Fold-change: -1.24E+00; Z-score: -1.26E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.70E-02; Fold-change: 3.49E-01; Z-score: 4.26E-01

Pituitary cancer [ICD-11: 2F37]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Pituitary
• The Specified Disease: Pituitary cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.73E-03; Fold-change: -5.56E-01; Z-score: -1.39E+00
• The Studied Tissue: Pituitary
• The Specified Disease: Pituitary gonadotrope tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.71E-01; Fold-change: -4.27E-02; Z-score: -9.64E-02

References

• Ref 1: Role of TGF-Beta1/Smad3-mediated fibrosis in drug resistance mechanism of prolactinoma .Brain Res. 2018 Nov 1;1698:204-212. doi: 10.1016/j.brainres.2018.07.024. Epub 2018 Jul 27. 10.1016/j.brainres.2018.07.024
• Ref 2: Overexpression of long non-coding RNA PVT1 in ovarian cancer cells promotes cisplatin resistance by regulating apoptotic pathways. Int J Clin Exp Med. 2015 Nov 15;8(11):20565-72. eCollection 2015.
• Ref 3: MicroRNA-574 enhances doxorubicin resistance through down-regulating SMAD4 in breast cancer cells. Eur Rev Med Pharmacol Sci. 2018 Mar;22(5):1342-1350. doi: 10.26355/eurrev_201803_14476.
• Ref 4: miR-509-5p and miR-1243 increase the sensitivity to gemcitabine by inhibiting epithelial-mesenchymal transition in pancreatic cancer. Sci Rep. 2017 Jun 21;7(1):4002. doi: 10.1038/s41598-017-04191-w.
• Ref 5: miR-146a suppresses the sensitivity to interferon-Alpha in hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2011 Nov 4;414(4):675-80. doi: 10.1016/j.bbrc.2011.09.124. Epub 2011 Oct 1.
• Ref 6: miR-19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4: validation by bioinformatics and experimental analyses. J Exp Clin Cancer Res. 2017 Sep 22;36(1):131. doi: 10.1186/s13046-017-0602-5.