Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHC33FF)

• DOT Name: Nidogen-2 (NID2)
• Synonyms: NID-2; Osteonidogen
• Gene Name: NID2
• Related Disease:
  Bladder cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Advanced cancer
  Craniofacial microsomia
  Digestive system neoplasm
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Gonorrhea
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Oral cavity squamous cell carcinoma
  Ovarian cancer
  Ovarian neoplasm
  Scleroderma
  Systemic sclerosis
  Transitional cell carcinoma
  Urothelial carcinoma
  Breast carcinoma
  Metastatic malignant neoplasm
  Nasopharyngeal carcinoma
  Stomach cancer
• UniProt ID: NID2_HUMAN
• Pfam ID: PF12662 ; PF12947 ; PF07645 ; PF07474 ; PF00058 ; PF06119 ; PF00086
• Sequence:
  MEGDRVAGRPVLSSLPVLLLLPLLMLRAAALHPDELFPHGESWGDQLLQEGDDESSAVVK
  LANPLHFYEARFSNLYVGTNGIISTQDFPRETQYVDYDFPTDFPAIAPFLADIDTSHGRG
  RVLYREDTSPAVLGLAARYVRAGFPRSARFTPTHAFLATWEQVGAYEEVKRGALPSGELN
  TFQAVLASDGSDSYALFLYPANGLQFLGTRPKESYNVQLQLPARVGFCRGEADDLKSEGP
  YFSLTSTEQSVKNLYQLSNLGIPGVWAFHIGSTSPLDNVRPAAVGDLSAAHSSVPLGRSF
  SHATALESDYNEDNLDYYDVNEEEAEYLPGEPEEALNGHSSIDVSFQSKVDTKPLEESST
  LDPHTKEGTSLGEVGGPDLKGQVEPWDERETRSPAPPEVDRDSLAPSWETPPPYPENGSI
  QPYPDGGPVPSEMDVPPAHPEEEIVLRSYPASGHTTPLSRGTYEVGLEDNIGSNTEVFTY
  NAANKETCEHNHRQCSRHAFCTDYATGFCCHCQSKFYGNGKHCLPEGAPHRVNGKVSGHL
  HVGHTPVHFTDVDLHAYIVGNDGRAYTAISHIPQPAAQALLPLTPIGGLFGWLFALEKPG
  SENGFSLAGAAFTHDMEVTFYPGEETVRITQTAEGLDPENYLSIKTNIQGQVPYVSANFT
  AHISPYKELYHYSDSTVTSTSSRDYSLTFGAINQTWSYRIHQNITYQVCRHAPRHPSFPT
  TQQLNVDRVFALYNDEERVLRFAVTNQIGPVKEDSDPTPGNPCYDGSHMCDTTARCHPGT
  GVDYTCECASGYQGDGRNCVDENECATGFHRCGPNSVCINLPGSYRCECRSGYEFADDRH
  TCILITPPANPCEDGSHTCAPAGQARCVHHGGSTFSCACLPGYAGDGHQCTDVDECSENR
  CHPAATCYNTPGSFSCRCQPGYYGDGFQCIPDSTSSLTPCEQQQRHAQAQYAYPGARFHI
  PQCDEQGNFLPLQCHGSTGFCWCVDPDGHEVPGTQTPPGSTPPHCGPSPEPTQRPPTICE
  RWRENLLEHYGGTPRDDQYVPQCDDLGHFIPLQCHGKSDFCWCVDKDGREVQGTRSQPGT
  TPACIPTVAPPMVRPTPRPDVTPPSVGTFLLYTQGQQIGYLPLNGTRLQKDAAKTLLSLH
  GSIIVGIDYDCRERMVYWTDVAGRTISRAGLELGAEPETIVNSGLISPEGLAIDHIRRTM
  YWTDSVLDKIESALLDGSERKVLFYTDLVNPRAIAVDPIRGNLYWTDWNREAPKIETSSL
  DGENRRILINTDIGLPNGLTFDPFSKLLCWADAGTKKLECTLPDGTGRRVIQNNLKYPFS
  IVSYADHFYHTDWRRDGVVSVNKHSGQFTDEYLPEQRSHLYGITAVYPYCPTGRK
• Function: Cell adhesion glycoprotein which is widely distributed in basement membranes. Binds to collagens I and IV, to perlecan and to laminin 1. Does not bind fibulins. It probably has a role in cell-extracellular matrix interactions.
• Tissue Specificity: Detected in placenta (at protein level) . Heart and bone. Less in pancreas, kidney and skeletal muscle.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway: Laminin interactions (R-HSA-3000157)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Definitive	Posttranslational Modification	[1]
Urinary bladder cancer	DISDV4T7	Definitive	Posttranslational Modification	[1]
Urinary bladder neoplasm	DIS7HACE	Definitive	Posttranslational Modification	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Craniofacial microsomia	DISYHJ2P	Strong	Genetic Variation	[3]
Digestive system neoplasm	DISPOJCT	Strong	Posttranslational Modification	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[7]
Gonorrhea	DISQ5AO6	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Posttranslational Modification	[8]
Lung carcinoma	DISTR26C	Strong	Posttranslational Modification	[8]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Oral cavity squamous cell carcinoma	DISQVJVA	Strong	Biomarker	[11]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[5]
Scleroderma	DISVQ342	Strong	Altered Expression	[12]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[12]
Transitional cell carcinoma	DISWVVDR	Strong	Posttranslational Modification	[1]
Urothelial carcinoma	DISRTNTN	Strong	Posttranslational Modification	[1]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[13]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[14]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[14]
Stomach cancer	DISKIJSX	Limited	Biomarker	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Nidogen-2 (NID2) affects the response to substance of Mitoxantrone.	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Nidogen-2 (NID2).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nidogen-2 (NID2).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nidogen-2 (NID2).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nidogen-2 (NID2).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Nidogen-2 (NID2).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Nidogen-2 (NID2).	[20]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Nidogen-2 (NID2).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Nidogen-2 (NID2).	[22]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Nidogen-2 (NID2).	[23]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Nidogen-2 (NID2).	[25]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Nidogen-2 (NID2).	[21]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Nidogen-2 (NID2).	[21]
Prednisolone	DMQ8FR2	Approved	Prednisolone increases the expression of Nidogen-2 (NID2).	[21]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone increases the expression of Nidogen-2 (NID2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nidogen-2 (NID2).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Nidogen-2 (NID2).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Nidogen-2 (NID2).	[30]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Nidogen-2 (NID2).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Nidogen-2 (NID2).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Nidogen-2 (NID2).	[27]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the secretion of Nidogen-2 (NID2).	[26]

References

• [1] Urinary NID2 and TWIST1 methylation to augment conventional urine cytology for the detection of bladder cancer.Cancer Biomark. 2017;18(4):381-387. doi: 10.3233/CBM-160261.
• [2] NID2 can serve as a potential prognosis prediction biomarker and promotes the invasion and migration of gastric cancer.Pathol Res Pract. 2019 Oct;215(10):152553. doi: 10.1016/j.prp.2019.152553. Epub 2019 Jul 23.
• [3] Genome-wide association study identifies multiple susceptibility loci for craniofacial microsomia.Nat Commun. 2016 Feb 8;7:10605. doi: 10.1038/ncomms10605.
• [4] Nidogen 1 and 2 gene promoters are aberrantly methylated in human gastrointestinal cancer.Mol Cancer. 2007 Feb 28;6:17. doi: 10.1186/1476-4598-6-17.
• [5] Evaluation of Serum Nidogen-2 as a Screening and Diagnostic Tool for Ovarian Cancer.Gynecol Obstet Invest. 2018;83(5):461-465. doi: 10.1159/000481798. Epub 2017 Nov 7.
• [6] Elevated levels of serum nidogen-2 in esophageal squamous cell carcinoma.Cancer Biomark. 2018 Feb 14;21(3):583-590. doi: 10.3233/CBM-170484.
• [7] Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in gastric cancer.Pathol Res Pract. 2019 May;215(5):1038-1048. doi: 10.1016/j.prp.2019.02.012. Epub 2019 Feb 28.
• [8] Silencing NID2 by DNA Hypermethylation Promotes Lung Cancer.Pathol Oncol Res. 2020 Apr;26(2):801-811. doi: 10.1007/s12253-019-00609-0. Epub 2019 Mar 2.
• [9] Hypermethylation of TWIST1 and NID2 in tumor tissues and voided urine in urinary bladder cancer patients.DNA Cell Biol. 2013 Jul;32(7):386-92. doi: 10.1089/dna.2013.2030. Epub 2013 May 19.
• [10] The more potential performance of nidogen 2 methylation by tissue or plasma DNA over brichoalveolar lavage DNA in diagnosis of nonsmall cell lung cancer.J Cancer Res Ther. 2018 Jun;14(Supplement):S341-S346. doi: 10.4103/0973-1482.235352.
• [11] NID2 and HOXA9 promoter hypermethylation as biomarkers for prevention and early detection in oral cavity squamous cell carcinoma tissues and saliva.Cancer Prev Res (Phila). 2011 Jul;4(7):1061-72. doi: 10.1158/1940-6207.CAPR-11-0006. Epub 2011 May 10.
• [12] Methyl-CpG-binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts.Ann Rheum Dis. 2018 Aug;77(8):1208-1218. doi: 10.1136/annrheumdis-2018-213022. Epub 2018 May 14.
• [13] Contribution of ADAMTS1 as a tumor suppressor gene in human breast carcinoma. Linking its tumor inhibitory properties to its proteolytic activity on nidogen-1 and nidogen-2.Int J Cancer. 2013 Nov 15;133(10):2315-24. doi: 10.1002/ijc.28271. Epub 2013 Jun 13.
• [14] Metastasis-suppressing NID2, an epigenetically-silenced gene, in the pathogenesis of nasopharyngeal carcinoma and esophageal squamous cell carcinoma.Oncotarget. 2016 Nov 29;7(48):78859-78871. doi: 10.18632/oncotarget.12889.
• [15] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [16] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [17] 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.
• [18] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [19] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [20] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [21] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [22] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [23] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [24] 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.
• [25] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [26] Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects. Biochim Biophys Acta. 2014 Sep;1844(9):1511-22. doi: 10.1016/j.bbapap.2014.04.023. Epub 2014 May 5.
• [27] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [28] 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.
• [29] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [30] 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.
• [31] 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.
• [32] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.