Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRI8EHN)

• DOT Name: Transmembrane 4 L6 family member 4 (TM4SF4)
• Synonyms: Intestine and liver tetraspan membrane protein; IL-TMP
• Gene Name: TM4SF4
• Related Disease:
  Neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Colorectal carcinoma
  Hepatocellular carcinoma
  Liver cancer
  Lung adenocarcinoma
  Lung carcinoma
  Non-small-cell lung cancer
  Polycystic ovarian syndrome
  Advanced cancer
• UniProt ID: T4S4_HUMAN
• Pfam ID: PF05805
• Sequence:
  MCTGGCARCLGGTLIPLAFFGFLANILLFFPGGKVIDDNDHLSQEIWFFGGILGSGVLMI
  FPALVFLGLKNNDCCGCCGNEGCGKRFAMFTSTIFAVVGFLGAGYSFIISAISINKGPKC
  LMANSTWGYPFHDGDYLNDEALWNKCREPLNVVPWNLTLFSILLVVGGIQMVLCAIQVVN
  GLLGTLCGDCQCCGCCGGDGPV
• Function: Regulates the adhesive and proliferative status of intestinal epithelial cells. Can mediate density-dependent cell proliferation.
• Tissue Specificity: Jejunum and liver.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Liver cancer	DISDE4BI	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Altered Expression	[6]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[5]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Transmembrane 4 L6 family member 4 (TM4SF4).	[7]

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transmembrane 4 L6 family member 4 (TM4SF4).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transmembrane 4 L6 family member 4 (TM4SF4).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transmembrane 4 L6 family member 4 (TM4SF4).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transmembrane 4 L6 family member 4 (TM4SF4).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transmembrane 4 L6 family member 4 (TM4SF4).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transmembrane 4 L6 family member 4 (TM4SF4).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transmembrane 4 L6 family member 4 (TM4SF4).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Transmembrane 4 L6 family member 4 (TM4SF4).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transmembrane 4 L6 family member 4 (TM4SF4).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transmembrane 4 L6 family member 4 (TM4SF4).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transmembrane 4 L6 family member 4 (TM4SF4).	[17]

References

• [1] Human tetraspanin transmembrane 4 superfamily member 4 or intestinal and liver tetraspan membrane protein is overexpressed in hepatocellular carcinoma and accelerates tumor cell growth.Acta Biochim Biophys Sin (Shanghai). 2012 Mar;44(3):224-32. doi: 10.1093/abbs/gmr124. Epub 2012 Jan 10.
• [2] Adenovirus-mediated delivery of siRNA targeting TM4SF4 attenuated liver cancer cell growth in vitro and in vivo.Acta Biochim Biophys Sin (Shanghai). 2013 Mar;45(3):213-9. doi: 10.1093/abbs/gms115. Epub 2013 Jan 7.
• [3] The integrated pathway of TGF/Snail with TNF/NFB may facilitate the tumor-stroma interaction in the EMT process and colorectal cancer prognosis.Sci Rep. 2017 Jul 7;7(1):4915. doi: 10.1038/s41598-017-05280-6.
• [4] TM4SF4 overexpression in radiation-resistant lung carcinoma cells activates IGF1R via elevation of IGF1.Oncotarget. 2014 Oct 30;5(20):9823-37. doi: 10.18632/oncotarget.2450.
• [5] Osteopontin production by TM4SF4 signaling drives a positive feedback autocrine loop with the STAT3 pathway to maintain cancer stem cell-like properties in lung cancer cells.Oncotarget. 2017 Sep 18;8(60):101284-101297. doi: 10.18632/oncotarget.21021. eCollection 2017 Nov 24.
• [6] Microarray evaluation of endometrial receptivity in Chinese women with polycystic ovary syndrome.Reprod Biomed Online. 2008 Sep;17(3):425-35. doi: 10.1016/s1472-6483(10)60228-3.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Gene expression profiling of A549 cells exposed to Milan PM2.5. Toxicol Lett. 2012 Mar 7;209(2):136-45.
• [17] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.