Details of Drug Off-Target (DOT)

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

• DOT Name: Integrin alpha-7 (ITGA7)
• Gene Name: ITGA7
• Related Disease:
  Congenital merosin-deficient muscular dystrophy 1A
  Adult glioblastoma
  Arteriosclerosis
  Breast cancer
  Breast carcinoma
  Campomelic dysplasia
  Carcinoma of liver and intrahepatic biliary tract
  Cardiomyopathy
  Central core myopathy
  Colon cancer
  Colonic neoplasm
  Congenital muscular dystrophy due to integrin alpha-7 deficiency
  Congenital myopathy
  Craniometaphyseal dysplasia, autosomal dominant
  Duchenne muscular dystrophy
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Idiopathic cardiomyopathy
  Liver cancer
  Malignant glioma
  Metastatic malignant neoplasm
  Multiminicore myopathy
  Myopathy
  Nemaline myopathy
  Non-small-cell lung cancer
  Renal cell carcinoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Lung cancer
  Lung carcinoma
  Muscular dystrophy
  Congenital fiber-type disproportion myopathy
  Asthma
  Advanced cancer
  Congenital muscular dystrophy
  Leiomyosarcoma
  Malignant pleural mesothelioma
  Neoplasm
  Prostate neoplasm
• UniProt ID: ITA7_HUMAN
• Pfam ID: PF01839 ; PF08441 ; PF20805 ; PF20806
• Sequence:
  MAGARSRDPWGASGICYLFGSLLVELLFSRAVAFNLDVMGALRKEGEPGSLFGFSVALHR
  QLQPRPQSWLLVGAPQALALPGQQANRTGGLFACPLSLEETDCYRVDIDQGADMQKESKE
  NQWLGVSVRSQGPGGKIVTCAHRYEARQRVDQILETRDMIGRCFVLSQDLAIRDELDGGE
  WKFCEGRPQGHEQFGFCQQGTAAAFSPDSHYLLFGAPGTYNWKGTARVELCAQGSADLAH
  LDDGPYEAGGEKEQDPRLIPVPANSYFGLLFVTNIDSSDPDQLVYKTLDPADRLPGPAGD
  LALNSYLGFSIDSGKGLVRAEELSFVAGAPRANHKGAVVILRKDSASRLVPEVMLSGERL
  TSGFGYSLAVADLNSDGWPDLIVGAPYFFERQEELGGAVYVYLNQGGHWAGISPLRLCGS
  PDSMFGISLAVLGDLNQDGFPDIAVGAPFDGDGKVFIYHGSSLGVVAKPSQVLEGEAVGI
  KSFGYSLSGSLDMDGNQYPDLLVGSLADTAVLFRARPILHVSHEVSIAPRSIDLEQPNCA
  GGHSVCVDLRVCFSYIAVPSSYSPTVALDYVLDADTDRRLRGQVPRVTFLSRNLEEPKHQ
  ASGTVWLKHQHDRVCGDAMFQLQENVKDKLRAIVVTLSYSLQTPRLRRQAPGQGLPPVAP
  ILNAHQPSTQRAEIHFLKQGCGEDKICQSNLQLVRARFCTRVSDTEFQPLPMDVDGTTAL
  FALSGQPVIGLELMVTNLPSDPAQPQADGDDAHEAQLLVMLPDSLHYSGVRALDPAEKPL
  CLSNENASHVECELGNPMKRGAQVTFYLILSTSGISIETTELEVELLLATISEQELHPVS
  ARARVFIELPLSIAGMAIPQQLFFSGVVRGERAMQSERDVGSKVKYEVTVSNQGQSLRTL
  GSAFLNIMWPHEIANGKWLLYPMQVELEGGQGPGQKGLCSPRPNILHLDVDSRDRRRREL
  EPPEQQEPGERQEPSMSWWPVSSAEKKKNITLDCARGTANCVVFSCPLYSFDRAAVLHVW
  GRLWNSTFLEEYSAVKSLEVIVRANITVKSSIKNLMLRDASTVIPVMVYLDPMAVVAEGV
  PWWVILLAVLAGLLVLALLVLLLWKMGFFKRAKHPEATVPQYHAVKIPREDRQQFKEEKT
  GTILRNNWGSPRREGPDAHPILAADGHPELGPDGHPGPGTA
• Function: Integrin alpha-7/beta-1 is the primary laminin receptor on skeletal myoblasts and adult myofibers. During myogenic differentiation, it may induce changes in the shape and mobility of myoblasts, and facilitate their localization at laminin-rich sites of secondary fiber formation. It is involved in the maintenance of the myofibers cytoarchitecture as well as for their anchorage, viability and functional integrity. Isoform Alpha-7X2B and isoform Alpha-7X1B promote myoblast migration on laminin 1 and laminin 2/4, but isoform Alpha-7X1B is less active on laminin 1 (In vitro). Acts as a Schwann cell receptor for laminin-2. Acts as a receptor of COMP and mediates its effect on vascular smooth muscle cells (VSMCs) maturation. Required to promote contractile phenotype acquisition in differentiated airway smooth muscle (ASM) cells.
• Tissue Specificity: Isoforms containing segment A are predominantly expressed in skeletal muscle. Isoforms containing segment B are abundantly expressed in skeletal muscle, moderately in cardiac muscle, small intestine, colon, ovary and prostate and weakly in lung and testes. Isoforms containing segment X2D are expressed at low levels in fetal and adult skeletal muscle and in cardiac muscle, but are not detected in myoblasts and myotubes. In muscle fibers isoforms containing segment A and B are expressed at myotendinous and neuromuscular junctions; isoforms containing segment C are expressed at neuromuscular junctions and at extrasynaptic sites. Isoforms containing segments X1 or X2 or, at low levels, X1X2 are expressed in fetal and adult skeletal muscle (myoblasts and myotubes) and cardiac muscle.
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Regulation of actin cytoskeleton (hsa04810)
  Cytoskeleton in muscle cells (hsa04820)
  Human papillomavirus infection (hsa05165)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  Laminin interactions (R-HSA-3000157)
  ECM proteoglycans (R-HSA-3000178)
  Integrin cell surface interactions (R-HSA-216083)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital merosin-deficient muscular dystrophy 1A	DISW3KEU	Definitive	Autosomal recessive	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Campomelic dysplasia	DISVTW53	Strong	Genetic Variation	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[6]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[7]
Central core myopathy	DIS18AZZ	Strong	Biomarker	[8]
Colon cancer	DISVC52G	Strong	Biomarker	[9]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[9]
Congenital muscular dystrophy due to integrin alpha-7 deficiency	DIS6HOFN	Strong	Autosomal recessive	[7]
Congenital myopathy	DISLSK9G	Strong	Biomarker	[8]
Craniometaphyseal dysplasia, autosomal dominant	DISU12OO	Strong	Genetic Variation	[5]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Biomarker	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[11]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Idiopathic cardiomyopathy	DISUGBZL	Strong	Therapeutic	[12]
Liver cancer	DISDE4BI	Strong	Altered Expression	[6]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[13]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[14]
Multiminicore myopathy	DISE6VYN	Strong	Biomarker	[8]
Myopathy	DISOWG27	Strong	Biomarker	[15]
Nemaline myopathy	DIS5IYLY	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[16]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[17]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[18]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[19]
Lung cancer	DISCM4YA	moderate	Genetic Variation	[20]
Lung carcinoma	DISTR26C	moderate	Genetic Variation	[20]
Muscular dystrophy	DISJD6P7	moderate	Biomarker	[15]
Congenital fiber-type disproportion myopathy	DISU9T2M	Supportive	Autosomal dominant	[7]
Asthma	DISW9QNS	Disputed	Altered Expression	[21]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[22]
Congenital muscular dystrophy	DISKY7OY	Limited	Biomarker	[1]
Leiomyosarcoma	DIS6COXM	Limited	Genetic Variation	[23]
Malignant pleural mesothelioma	DIST2R60	Limited	Posttranslational Modification	[24]
Neoplasm	DISZKGEW	Limited	Altered Expression	[18]
Prostate neoplasm	DISHDKGQ	Limited	Genetic Variation	[23]

2 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 Integrin alpha-7 (ITGA7).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Integrin alpha-7 (ITGA7).	[36]

15 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 Integrin alpha-7 (ITGA7).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Integrin alpha-7 (ITGA7).	[27]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Integrin alpha-7 (ITGA7).	[28]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Integrin alpha-7 (ITGA7).	[29]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Integrin alpha-7 (ITGA7).	[30]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Integrin alpha-7 (ITGA7).	[31]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Integrin alpha-7 (ITGA7).	[32]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Integrin alpha-7 (ITGA7).	[33]
Sevoflurane	DMC9O43	Approved	Sevoflurane decreases the expression of Integrin alpha-7 (ITGA7).	[34]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Integrin alpha-7 (ITGA7).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Integrin alpha-7 (ITGA7).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Integrin alpha-7 (ITGA7).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Integrin alpha-7 (ITGA7).	[39]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Integrin alpha-7 (ITGA7).	[40]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Integrin alpha-7 (ITGA7).	[29]

References

• [1] Mutations in the integrin alpha7 gene cause congenital myopathy. Nat Genet. 1998 May;19(1):94-7. doi: 10.1038/ng0598-94.
• [2] A rapid in vitro methodology for simultaneous target discovery and antibody generation against functional cell subpopulations.Sci Rep. 2019 Jan 29;9(1):842. doi: 10.1038/s41598-018-37462-1.
• [3] Regulation of alpha7-integrin expression in vascular smooth muscle by injury-induced atherosclerosis.Am J Physiol Heart Circ Physiol. 2004 Jul;287(1):H381-9. doi: 10.1152/ajpheart.00939.2003. Epub 2004 Feb 26.
• [4] Integrin 7 high expression correlates with deteriorative tumor features and worse overall survival, and its knockdown inhibits cell proliferation and invasion but increases apoptosis in breast cancer.J Clin Lab Anal. 2019 Oct;33(8):e22979. doi: 10.1002/jcla.22979. Epub 2019 Jul 19.
• [5] Diagnosis and etiology of congenital muscular dystrophy.Neurology. 2008 Jul 29;71(5):312-21. doi: 10.1212/01.wnl.0000284605.27654.5a. Epub 2007 Dec 26.
• [6] Integrin alpha 7 correlates with poor clinical outcomes, and it regulates cell proliferation, apoptosis and stemness via PTK2-PI3K-Akt signaling pathway in hepatocellular carcinoma.Cell Signal. 2020 Feb;66:109465. doi: 10.1016/j.cellsig.2019.109465. Epub 2019 Nov 5.
• [7] Digenic mutational inheritance of the integrin alpha 7 and the myosin heavy chain 7B genes causes congenital myopathy with left ventricular non-compact cardiomyopathy. Orphanet J Rare Dis. 2013 Jun 21;8:91. doi: 10.1186/1750-1172-8-91.
• [8] 61 and 71 integrins are required in Schwann cells to sort axons.J Neurosci. 2013 Nov 13;33(46):17995-8007. doi: 10.1523/JNEUROSCI.3179-13.2013.
• [9] Global gene expression analysis of rat colon cancers induced by a food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.Carcinogenesis. 2004 Aug;25(8):1495-505. doi: 10.1093/carcin/bgh155. Epub 2004 Apr 1.
• [10] Human 7 Integrin Gene (ITGA7) Delivered by Adeno-Associated Virus Extends Survival of Severely Affected Dystrophin/Utrophin-Deficient Mice.Hum Gene Ther. 2015 Oct;26(10):647-56. doi: 10.1089/hum.2015.062. Epub 2015 Aug 11.
• [11] Integrin 7 is a functional cancer stem cell surface marker in oesophageal squamous cell carcinoma.Nat Commun. 2016 Dec 7;7:13568. doi: 10.1038/ncomms13568.
• [12] Transgenic expression of {alpha}7{beta}1 integrin maintains muscle integrity, increases regenerative capacity, promotes hypertrophy, and reduces cardiomyopathy in dystrophic mice.Am J Pathol. 2005 Jan;166(1):253-63. doi: 10.1016/s0002-9440(10)62249-3.
• [13] Integrin 7 Is a Functional Marker and Potential Therapeutic Target in Glioblastoma.Cell Stem Cell. 2017 Jul 6;21(1):35-50.e9. doi: 10.1016/j.stem.2017.04.009. Epub 2017 Jun 9.
• [14] Potential markers of tongue tumor progression selected by cDNA microarray.Int J Immunopathol Pharmacol. 2005 Jul-Sep;18(3):513-24. doi: 10.1177/039463200501800311.
• [15] Integrin alpha 7 beta 1 in muscular dystrophy/myopathy of unknown etiology.Am J Pathol. 2002 Jun;160(6):2135-43. doi: 10.1016/s0002-9440(10)61162-5.
• [16] Correlation of integrin alpha 7 with clinicopathological characteristics and survival profiles, as well as its regulatory role in cell proliferation, apoptosis, and stemness in non-small-cell lung cancer.J Clin Lab Anal. 2019 Oct;33(8):e22973. doi: 10.1002/jcla.22973. Epub 2019 Aug 16.
• [17] Acquired resistance to temsirolimus is associated with integrin 7 driven chemotactic activity of renal cell carcinoma in vitro.Oncotarget. 2018 Apr 10;9(27):18747-18759. doi: 10.18632/oncotarget.24650. eCollection 2018 Apr 10.
• [18] Integrin 7 is overexpressed and correlates with higher pathological grade, increased T stage, advanced TNM stage as well as worse survival in clear cell renal cell carcinoma patients: A retrospective study.J Clin Lab Anal. 2020 Jan;34(1):e23034. doi: 10.1002/jcla.23034. Epub 2019 Nov 11.
• [19] Circ-ITGA7 sponges miR-3187-3p to upregulate ASXL1, suppressing colorectal cancer proliferation.Cancer Manag Res. 2019 Jul 12;11:6499-6509. doi: 10.2147/CMAR.S203137. eCollection 2019.
• [20] S100P interacts with integrin 7 and increases cancer cell migration and invasion in lung cancer.Oncotarget. 2015 Oct 6;6(30):29585-98. doi: 10.18632/oncotarget.4987.
• [21] Integrin 7 expression is increased in asthmatic patients and its inhibition reduces Kras protein abundance in airway smooth muscle cells.Sci Rep. 2019 Jul 9;9(1):9892. doi: 10.1038/s41598-019-46260-2.
• [22] Integrin 7 correlates with worse clinical features and prognosis, and its knockdown inhibits cell proliferation and stemness in tongue squamous cell carcinoma.Int J Oncol. 2020 Jan;56(1):69-84. doi: 10.3892/ijo.2019.4927. Epub 2019 Nov 29.
• [23] Analysis of integrin alpha7 mutations in prostate cancer, liver cancer, glioblastoma multiforme, and leiomyosarcoma.J Natl Cancer Inst. 2007 Jun 6;99(11):868-80. doi: 10.1093/jnci/djk199.
• [24] Epigenetic down-regulation of integrin 7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma.J Pathol. 2015 Oct;237(2):203-14. doi: 10.1002/path.4567. Epub 2015 Jul 14.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [29] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [30] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [31] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [32] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [33] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [34] The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
• [35] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [36] 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.
• [37] 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.
• [38] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [39] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [40] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.