Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRPD9MI)

• DOT Name: Paired box protein Pax-8 (PAX8)
• Gene Name: PAX8
• Related Disease:
  Childhood kidney Wilms tumor
  Colorectal carcinoma
  Hypothyroidism, congenital, nongoitrous, 2
  Adenoma
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Colorectal neoplasm
  Congenital hypothyroidism
  Endometrial carcinoma
  Graves disease
  Hepatocellular carcinoma
  Hyperthyroidism
  Lung carcinoma
  Medullary thyroid gland carcinoma
  Mesothelioma
  Metastatic malignant neoplasm
  Neuroendocrine neoplasm
  Non-small-cell lung cancer
  Ovarian serous adenocarcinoma
  Renal cell carcinoma
  Serous cystadenocarcinoma
  Thyroid gland follicular carcinoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Wilms tumor
  Hypothyroidism
  Athyreosis
  Thyroid hypoplasia
  Clear cell renal carcinoma
  Goiter
  Kidney neoplasm
  Lung cancer
  Pancreatic cancer
  Thyroid cancer
  Thyroid gland carcinoma
• UniProt ID: PAX8_HUMAN
• PDB ID: 2K27
• Pfam ID: PF00292 ; PF12403
• Sequence:
  MPHNSIRSGHGGLNQLGGAFVNGRPLPEVVRQRIVDLAHQGVRPCDISRQLRVSHGCVSK
  ILGRYYETGSIRPGVIGGSKPKVATPKVVEKIGDYKRQNPTMFAWEIRDRLLAEGVCDND
  TVPSVSSINRIIRTKVQQPFNLPMDSCVATKSLSPGHTLIPSSAVTPPESPQSDSLGSTY
  SINGLLGIAQPGSDKRKMDDSDQDSCRLSIDSQSSSSGPRKHLRTDAFSQHHLEPLECPF
  ERQHYPEAYASPSHTKGEQGLYPLPLLNSTLDDGKATLTPSNTPLGRNLSTHQTYPVVAD
  PHSPFAIKQETPEVSSSSSTPSSLSSSAFLDLQQVGSGVPPFNAFPHAASVYGQFTGQAL
  LSGREMVGPTLPGYPPHIPTSGQGSYASSAIAGMVAGSEYSGNAYGHTPYSSYSEAWRFP
  NSSLLSSPYYYSSTSRPSAPPTTATAFDHL
• Function: Transcription factor for the thyroid-specific expression of the genes exclusively expressed in the thyroid cell type, maintaining the functional differentiation of such cells.
• Tissue Specificity: Expressed in the excretory system, thyroid gland and Wilms tumors.
• KEGG Pathway:
  Thyroid hormone synthesis (hsa04918)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Thyroid cancer (hsa05216)
• Reactome Pathway: Formation of intermediate mesoderm (R-HSA-9761174)

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Childhood kidney Wilms tumor	DIS0NMK3	Definitive	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[2]
Hypothyroidism, congenital, nongoitrous, 2	DISS8CHO	Definitive	Autosomal dominant	[3]
Adenoma	DIS78ZEV	Strong	Genetic Variation	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Cervical cancer	DISFSHPF	Strong	Biomarker	[7]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[7]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[2]
Congenital hypothyroidism	DISL5XVU	Strong	Genetic Variation	[8]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[9]
Graves disease	DISU4KOQ	Strong	Genetic Variation	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Hyperthyroidism	DISX87ZH	Strong	Biomarker	[12]
Lung carcinoma	DISTR26C	Strong	Biomarker	[13]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Genetic Variation	[14]
Mesothelioma	DISKWK9M	Strong	Genetic Variation	[15]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[6]
Neuroendocrine neoplasm	DISNPLOO	Strong	Biomarker	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[17]
Ovarian serous adenocarcinoma	DISSU72Z	Strong	Biomarker	[18]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[13]
Serous cystadenocarcinoma	DISVK716	Strong	Biomarker	[19]
Thyroid gland follicular carcinoma	DISFK2QT	Strong	Genetic Variation	[20]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Altered Expression	[21]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Wilms tumor	DISB6T16	Strong	Altered Expression	[1]
Hypothyroidism	DISR0H6D	moderate	Biomarker	[12]
Athyreosis	DISBHHCU	Supportive	Autosomal dominant	[22]
Thyroid hypoplasia	DISJG17B	Supportive	Autosomal dominant	[23]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[24]
Goiter	DISLCGI6	Limited	Genetic Variation	[25]
Kidney neoplasm	DISBNZTN	Limited	Biomarker	[26]
Lung cancer	DISCM4YA	Limited	Biomarker	[13]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[27]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[28]
Thyroid gland carcinoma	DISMNGZ0	Limited	Biomarker	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Paired box protein Pax-8 (PAX8) affects the response to substance of Cisplatin.	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Paired box protein Pax-8 (PAX8).	[29]
Folic acid	DMEMBJC	Approved	Folic acid affects the methylation of Paired box protein Pax-8 (PAX8).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Paired box protein Pax-8 (PAX8).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Paired box protein Pax-8 (PAX8).	[30]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Paired box protein Pax-8 (PAX8).	[31]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Paired box protein Pax-8 (PAX8).	[32]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Paired box protein Pax-8 (PAX8).	[34]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Paired box protein Pax-8 (PAX8).	[35]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Paired box protein Pax-8 (PAX8).	[36]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Paired box protein Pax-8 (PAX8).	[37]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Paired box protein Pax-8 (PAX8).	[38]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Paired box protein Pax-8 (PAX8).	[40]

References

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• [2] Genome-wide significant risk associations for mucinous ovarian carcinoma.Nat Genet. 2015 Aug;47(8):888-97. doi: 10.1038/ng.3336. Epub 2015 Jun 15.
• [3] PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet. 1998 May;19(1):83-6. doi: 10.1038/ng0598-83.
• [4] PAX8 mutation disturbing thyroid follicular growth: a case report.J Clin Endocrinol Metab. 2011 Dec;96(12):E2039-44. doi: 10.1210/jc.2011-1114. Epub 2011 Oct 5.
• [5] Vasitis nodosa and related lesions: a modern immunohistochemical staining profile with special emphasis on novel diagnostic dilemmas.Hum Pathol. 2018 Mar;73:164-170. doi: 10.1016/j.humpath.2017.12.001. Epub 2017 Dec 11.
• [6] Unexpected PAX8 Immunoreactivity in Metastatic High-grade Breast Cancer.Appl Immunohistochem Mol Morphol. 2019 Oct;27(9):637-643. doi: 10.1097/PAI.0000000000000707.
• [7] Expression quantitative trait loci in long non-coding RNA PAX8-AS1 are associated with decreased risk of cervical cancer.Mol Genet Genomics. 2016 Aug;291(4):1743-8. doi: 10.1007/s00438-016-1217-9. Epub 2016 May 25.
• [8] Systematic alanine scanning of PAX8 paired domain reveals functional importance of the N-subdomain.J Mol Endocrinol. 2019 Apr 1;62(3):129-135. doi: 10.1530/JME-18-0207.
• [9] Role of epithelial-mesenchymal transition factors in the histogenesis of uterine carcinomas.Virchows Arch. 2019 Jul;475(1):85-94. doi: 10.1007/s00428-019-02532-w. Epub 2019 Feb 9.
• [10] Evaluation of peroxisome proliferator-activated receptor-gamma expression in benign and malignant thyroid pathologies.Thyroid. 2005 Sep;15(9):997-1003. doi: 10.1089/thy.2005.15.997.
• [11] HBx regulates transcription factor PAX8 stabilization to promote the progression of hepatocellular carcinoma.Oncogene. 2019 Oct;38(40):6696-6710. doi: 10.1038/s41388-019-0907-2. Epub 2019 Aug 7.
• [12] Inadequate control of thyroid hormones sensitizes to hepatocarcinogenesis and unhealthy aging.Aging (Albany NY). 2019 Sep 13;11(18):7746-7779. doi: 10.18632/aging.102285. Epub 2019 Sep 13.
• [13] Immunohistochemical profiles in primary lung cancers and epithelial pulmonary metastases.Hum Pathol. 2019 Feb;84:221-230. doi: 10.1016/j.humpath.2018.10.009. Epub 2018 Oct 31.
• [14] Intragenic mutations in thyroid cancer.Endocrinol Metab Clin North Am. 2008 Jun;37(2):333-62, viii. doi: 10.1016/j.ecl.2008.02.004.
• [15] Immunohistochemistry in Peritoneal Mesothelioma: A Single-Center Experience of 244 Cases.Arch Pathol Lab Med. 2018 Feb;142(2):236-242. doi: 10.5858/arpa.2017-0092-OA. Epub 2017 Oct 19.
• [16] The Diagnostic Utility of PAX8 for Neuroendocrine Tumors: An Immunohistochemical Reappraisal.Appl Immunohistochem Mol Morphol. 2016 Jan;24(1):57-63. doi: 10.1097/PAI.0000000000000149.
• [17] Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non-small cell lung cancer.BMC Cancer. 2014 Mar 14;14:185. doi: 10.1186/1471-2407-14-185.
• [18] PAX8 Expression in a Subset of Malignant Peritoneal Mesotheliomas and Benign Mesothelium has Diagnostic Implications in the Differential Diagnosis of Ovarian Serous Carcinoma.Am J Surg Pathol. 2017 Dec;41(12):1675-1682. doi: 10.1097/PAS.0000000000000935.
• [19] Aberrant Pax-8 expression in well-differentiated papillary mesothelioma and malignant mesothelioma of the peritoneum: a clinicopathologic study.Hum Pathol. 2018 Feb;72:160-166. doi: 10.1016/j.humpath.2017.10.036. Epub 2017 Dec 11.
• [20] Genomic binding of PAX8-PPARG fusion protein regulates cancer-related pathways and alters the immune landscape of thyroid cancer.Oncotarget. 2017 Jan 24;8(4):5761-5773. doi: 10.18632/oncotarget.14050.
• [21] PAX8 expression in anaplastic thyroid carcinoma is less than those reported in early studies: a multi-institutional study of 182 cases using the monoclonal antibody MRQ-50.Virchows Arch. 2020 Mar;476(3):431-437. doi: 10.1007/s00428-019-02708-4. Epub 2019 Nov 16.
• [22] Genetic Defects in Thyroid Hormone Supply. 2018 Jan 12. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrre B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000C.
• [23] Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. J Clin Endocrinol Metab. 2001 Jan;86(1):234-8. doi: 10.1210/jcem.86.1.7140.
• [24] PAX8 activates metabolic genes via enhancer elements in Renal Cell Carcinoma.Nat Commun. 2019 Aug 20;10(1):3739. doi: 10.1038/s41467-019-11672-1.
• [25] Screening for mutations in transcription factors in a Czech cohort of 170 patients with congenital and early-onset hypothyroidism: identification of a novel PAX8 mutation in dominantly inherited early-onset non-autoimmune hypothyroidism.Eur J Endocrinol. 2007 May;156(5):521-9. doi: 10.1530/EJE-06-0709.
• [26] Immunohistochemical Profile of 20 Feline Renal Cell Carcinomas.J Comp Pathol. 2017 Aug-Oct;157(2-3):115-125. doi: 10.1016/j.jcpa.2017.06.004. Epub 2017 Jul 26.
• [27] Silencing of long noncoding RNA LINC00958 prevents tumor initiation of pancreatic cancer by acting as a sponge of microRNA-330-5p to down-regulate PAX8.Cancer Lett. 2019 Apr 1;446:49-61. doi: 10.1016/j.canlet.2018.12.017. Epub 2019 Jan 9.
• [28] Low dose radiation regulates BRAF-induced thyroid cellular dysfunction and transformation.Cell Commun Signal. 2019 Feb 13;17(1):12. doi: 10.1186/s12964-019-0322-x.
• [29] 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.
• [30] Multifaceted suppression of aggressive behavior of thyroid carcinoma by all-trans retinoic acid induced re-differentiation. Mol Cell Endocrinol. 2012 Jan 2;348(1):260-9. doi: 10.1016/j.mce.2011.09.002. Epub 2011 Sep 6.
• [31] 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.
• [32] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [33] The long-term impact of folic acid in pregnancy on offspring DNA methylation: follow-up of the Aberdeen Folic Acid Supplementation Trial (AFAST). Int J Epidemiol. 2018 Jun 1;47(3):928-937. doi: 10.1093/ije/dyy032.
• [34] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [35] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [36] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [37] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [38] Resveratrol induces differentiation markers expression in anaplastic thyroid carcinoma via activation of Notch1 signaling and suppresses cell growth. Mol Cancer Ther. 2013 Jul;12(7):1276-87. doi: 10.1158/1535-7163.MCT-12-0841. Epub 2013 Apr 17.
• [39] 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.
• [40] Expression, regulation, and function of paired-box gene 8 in the human placenta and placental cancer cell lines. Endocrinology. 2005 Sep;146(9):4009-15. doi: 10.1210/en.2005-0084. Epub 2005 Jun 16.
• [41] 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.