Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQV7BKQ)

• DOT Name: Kunitz-type protease inhibitor 2 (SPINT2)
• Synonyms: Hepatocyte growth factor activator inhibitor type 2; HAI-2; Placental bikunin
• Gene Name: SPINT2
• Related Disease:
  Placenta disorder
  Adenocarcinoma
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cervical cancer
  Cervical carcinoma
  Cocaine addiction
  Congenital secretory sodium diarrhea 3
  Endometrial carcinoma
  Esophageal squamous cell carcinoma
  Gastric cancer
  Glioma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Medulloblastoma
  Nasopharyngeal carcinoma
  Neoplasm
  Neural tube defect
  Non-small-cell lung cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Epithelial ovarian cancer
  Melanoma
  Ovarian cancer
  Polydactyly
  Undifferentiated carcinoma
  Carcinoma
  Clear cell renal carcinoma
  Coloboma of optic nerve
  Colorectal carcinoma
  Congenital sodium diarrhea
  Glioblastoma multiforme
  Pancreatic cancer
  Renal cell carcinoma
• UniProt ID: SPIT2_HUMAN
• PDB ID: 4U32
• Pfam ID: PF00014
• Sequence:
  MAQLCGLRRSRAFLALLGSLLLSGVLAADRERSIHDFCLVSKVVGRCRASMPRWWYNVTD
  GSCQLFVYGGCDGNSNNYLTKEECLKKCATVTENATGDLATSRNAADSSVPSAPRRQDSE
  DHSSDMFNYEEYCTANAVTGPCRASFPRWYFDVERNSCNNFIYGGCRGNKNSYRSEEACM
  LRCFRQQENPPLPLGSKVVVLAGLFVMVLILFLGASMVYLIRVARRNQERALRTVWSSGD
  DKEQLVKNTYVL
• Function: Inhibitor of HGFAC. Also inhibits plasmin, and plasma and tissue kallikrein. Inhibits serine protease activity of TMPRSS13. Inhibits serine protease activity of ST14/matriptase in vitro.
• Tissue Specificity: Expressed in placenta, kidney, pancreas, prostate, testis, thymus, and trachea.
• Reactome Pathway:
  Signaling by MST1 (R-HSA-8852405)
  MET Receptor Activation (R-HSA-6806942)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Placenta disorder	DISUW4CP	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Adult glioblastoma	DISVP4LU	Strong	Posttranslational Modification	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Cervical cancer	DISFSHPF	Strong	Posttranslational Modification	[7]
Cervical carcinoma	DIST4S00	Strong	Posttranslational Modification	[7]
Cocaine addiction	DISHTRXG	Strong	Biomarker	[8]
Congenital secretory sodium diarrhea 3	DISAF31B	Strong	Autosomal recessive	[9]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Posttranslational Modification	[11]
Gastric cancer	DISXGOUK	Strong	Posttranslational Modification	[12]
Glioma	DIS5RPEH	Strong	Biomarker	[13]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[14]
Lung cancer	DISCM4YA	Strong	Altered Expression	[15]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[15]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[16]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[17]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Neural tube defect	DIS5J95E	Strong	Altered Expression	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[19]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[20]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[21]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[21]
Stomach cancer	DISKIJSX	Strong	Posttranslational Modification	[12]
Epithelial ovarian cancer	DIS56MH2	moderate	Altered Expression	[20]
Melanoma	DIS1RRCY	moderate	Biomarker	[22]
Ovarian cancer	DISZJHAP	moderate	Altered Expression	[20]
Polydactyly	DIS25BMZ	moderate	Biomarker	[23]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[24]
Carcinoma	DISH9F1N	Limited	Biomarker	[24]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[25]
Coloboma of optic nerve	DISR9DCH	Limited	Genetic Variation	[26]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[27]
Congenital sodium diarrhea	DISDXE72	Limited	Genetic Variation	[26]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[4]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[27]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[30]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[31]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[32]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[33]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[34]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[35]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[28]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[32]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[36]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[37]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[38]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[40]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[41]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Kunitz-type protease inhibitor 2 (SPINT2).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Kunitz-type protease inhibitor 2 (SPINT2).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Kunitz-type protease inhibitor 2 (SPINT2).	[42]

References

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• [2] Differential gene expression in human lung adenocarcinomas and squamous cell carcinomas.Clin Cancer Res. 2002 Apr;8(4):1127-38.
• [3] Aberrant methylation and silencing of the SPINT2 gene in high-grade gliomas.Cancer Sci. 2018 Sep;109(9):2970-2979. doi: 10.1111/cas.13732. Epub 2018 Aug 16.
• [4] SPINT2 is hypermethylated in both IDH1 mutated and wild-type glioblastomas, and exerts tumor suppression via reduction of c-Met activation.J Neurooncol. 2019 May;142(3):423-434. doi: 10.1007/s11060-019-03126-x. Epub 2019 Mar 5.
• [5] The hepatocyte growth factor regulatory factors in human breast cancer.Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):202-11. doi: 10.1158/1078-0432.ccr-0553-3.
• [6] Regulation of hepatocyte growth factor activator inhibitor 2 by hypoxia in breast cancer.Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):550-8. doi: 10.1158/1078-0432.CCR-06-1266.
• [7] Study on the methylation status of SPINT2 gene and its expression in cervical carcinoma.Cancer Biomark. 2018;22(3):435-442. doi: 10.3233/CBM-171050.
• [8] Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence.Neuropsychopharmacology. 2018 Mar;43(4):928. doi: 10.1038/npp.2017.245.
• [9] Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form. Hum Genet. 2014 Mar;133(3):299-310. doi: 10.1007/s00439-013-1380-6. Epub 2013 Oct 19.
• [10] The role of hepatocyte growth factor activator inhibitor (HAI)-1 and HAI-2 in endometrial cancer.Int J Cancer. 2011 Jun 1;128(11):2613-24. doi: 10.1002/ijc.25606. Epub 2010 Oct 4.
• [11] Epigenetic inactivation of SPINT2 is associated with tumor suppressive function in esophageal squamous cell carcinoma.Exp Cell Res. 2014 Mar 10;322(1):149-58. doi: 10.1016/j.yexcr.2013.11.009. Epub 2013 Nov 21.
• [12] Epigenetic inactivation and tumor suppressor activity of HAI-2/SPINT2 in gastric cancer.Int J Cancer. 2010 Oct 1;127(7):1526-34. doi: 10.1002/ijc.25161.
• [13] Loss of SPINT2 expression frequently occurs in glioma, leading to increased growth and invasion via MMP2.Cell Oncol (Dordr). 2020 Feb;43(1):107-121. doi: 10.1007/s13402-019-00475-7. Epub 2019 Nov 7.
• [14] Aberrant methylation of promoter region of SPINT2/HAI-2 gene: an epigenetic mechanism in hepatitis C virus-induced hepatocarcinogenesis.Genet Test Mol Biomarkers. 2015 Jul;19(7):399-404. doi: 10.1089/gtmb.2015.0025. Epub 2015 Jun 1.
• [15] HAI-2 as a novel inhibitor of plasmin represses lung cancer cell invasion and metastasis.Br J Cancer. 2019 Mar;120(5):499-511. doi: 10.1038/s41416-019-0400-2. Epub 2019 Feb 15.
• [16] Molecular genetic analysis of the hepatocyte growth factor/MET signaling pathway in pediatric medulloblastoma.Genes Chromosomes Cancer. 2012 Jul;51(7):675-88. doi: 10.1002/gcc.21954. Epub 2012 Mar 23.
• [17] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [18] CSF-Based Analysis for Identification of Potential Serum Biomarkers of Neural Tube Defects.Neurosci Bull. 2017 Aug;33(4):436-444. doi: 10.1007/s12264-017-0154-x. Epub 2017 Jul 10.
• [19] STYK1 promotes tumor growth and metastasis by reducing SPINT2/HAI-2 expression in non-small cell lung cancer.Cell Death Dis. 2019 Jun 4;10(6):435. doi: 10.1038/s41419-019-1659-1.
• [20] Expression of hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) in ovarian cancer.Int J Oncol. 2009 Feb;34(2):345-53.
• [21] Analysis of Over 140,000 European Descendants Identifies Genetically Predicted Blood Protein Biomarkers Associated with Prostate Cancer Risk.Cancer Res. 2019 Sep 15;79(18):4592-4598. doi: 10.1158/0008-5472.CAN-18-3997. Epub 2019 Jul 23.
• [22] Epigenetic Silencing of SPINT2 Promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma.J Invest Dermatol. 2015 Sep;135(9):2283-2291. doi: 10.1038/jid.2015.160. Epub 2015 Apr 24.
• [23] A new syndrome of tufting enteropathy and choanal atresia, with ophthalmologic, hematologic and hair abnormalities.Clin Dysmorphol. 2007 Oct;16(4):211-21. doi: 10.1097/MCD.0b013e328274264b.
• [24] Global gene expression profiling of chemically induced rat mammary gland carcinomas and adenomas.Toxicol Pathol. 2005;33(7):768-75. doi: 10.1080/01926230500437027.
• [25] Dysregulated HAI-2 Plays an Important Role in Renal Cell Carcinoma Bone Metastasis through Ligand-Dependent MET Phosphorylation.Cancers (Basel). 2018 Jun 8;10(6):190. doi: 10.3390/cancers10060190.
• [26] Congenital sodium diarrhea and chorioretinal coloboma with optic disc coloboma in a patient with biallelic SPINT2 mutations, including p.(Tyr163Cys).Am J Med Genet A. 2018 Apr;176(4):997-1000. doi: 10.1002/ajmg.a.38637.
• [27] Conserved expression of hepatocyte growth factor activator inhibitor type-2/placental bikunin in human colorectal carcinomas.Cancer Lett. 2000 Feb 1;148(2):127-34. doi: 10.1016/s0304-3835(99)00322-5.
• [28] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [29] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [30] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [31] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [32] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [33] 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.
• [34] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [35] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [36] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [37] Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-659. doi: 10.1016/j.cell.2009.06.034. Epub 2009 Aug 13.
• [38] Casodex treatment induces hypoxia-related gene expression in the LNCaP prostate cancer progression model. BMC Urol. 2005 Mar 24;5:5.
• [39] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [40] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [41] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [42] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [43] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.