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Screening for the 3' UTR Polymorphism of the PXR Gene in South Indian Breast Cancer Patients and its Potential role in Pharmacogenomics

  • Revathidevi, Sundaramoorthy (Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras) ;
  • Sudesh, Ravi (Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras) ;
  • Vaishnavi, Varadharajan (Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras) ;
  • Kaliyanasundaram, Muthukrishnan (Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras) ;
  • MaryHelen, Kilyara George (Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras) ;
  • Sukanya, Ganesan (Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras) ;
  • Munirajan, Arasambattu Kannan (Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras)
  • Published : 2016.08.01

Abstract

Background: Breast cancer, the commonest cancer among women in the world, ranks top in India with an incidence rate of 1,45,000 new cases and mortality rate of 70,000 women every year. Chemotherapy outcome for breast cancer is hampered due to poor response and irreversible dose-dependent cardiotoxicity which is determined by genetic variations in drug metabolizing enzymes and transporters. Pregnane X receptor (PXR), a member of the nuclear receptor superfamily, induces expression of drug metabolizing enzymes (DMEs) and transporters leading to regulation of xenobiotic metabolism. Materials and Methods: A genomic region spanning PXR 3' UTR was amplified and sequenced using genomic DNA isolated from 96 South Indian breast cancer patients. Genetic variants observed in our study subjects were queried in miRSNP to establish SNPs that alter miRNA binding sites in PXR 3' UTR. In addition, enrichment analysis was carried out to understand the network of miRNAs and PXR in drug metabolism using DIANA miRpath and miRwalk pathway prediction tools. Results: In this study, we identified SNPs rs3732359, rs3732360, rs1054190, rs1054191 and rs6438550 in the PXR 3; UTR region. The SNPs rs3732360, rs1054190 and rs1054191 were located in the binding site of miR-500a-3p, miR-532-3p and miR-374a-3p resulting in the altered PXR level due to the deregulation of post-transcriptional control and this leads to poor treatment response and toxicity. Conclusions: Genetic variants identified in PXR 3' UTR and their effects on PXR levels through post-transcriptional regulation provide a genetic basis for interindividual variability in treatment response and toxicity associated with chemotherapy.

Keywords

Pregnane X receptor;3' UTR variation;MiRSNPs;drug metabolism;doxorubicin;cardiotoxicity

Acknowledgement

Supported by : Board of Research in Nuclear Sciences

References

  1. Cakmak HA, Coskunpinar E, Ikitimur B, et al (2015). The prognostic value of circulating microRNAs in heart failure: preliminary results from a genome-wide expression study. J Cardiovasc Med, 16, 431-7. https://doi.org/10.2459/JCM.0000000000000233
  2. Chang YY, Kuo WH, Hung JH, et al (2015). Deregulated microRNAs in triple-negative breast cancer revealed by deep sequencing. Mol Cancer, 14, 36. https://doi.org/10.1186/s12943-015-0301-9
  3. Chavali V, Tyagi SC, Mishra PK (2014). Differential expression of dicer, miRNAs, and inflammatory markers in diabetic Ins2+/− Akita hearts. Cell Biochem Biophys, 68, 25-35. https://doi.org/10.1007/s12013-013-9679-4
  4. Chen Y, Tang Y, Chen S, Nie D (2009). Regulation of drug resistance by human pregnane X receptor in breast cancer. Cancer Biol Ther, 8, 1265-72. https://doi.org/10.4161/cbt.8.13.8696
  5. Conde I, Lobo MV, Zamora J, et al (2008). Human pregnane X receptor is expressed in breast carcinomas, potential heterodimers formation between hPXR and RXR-alpha. BMC Cancer, 8, 174. https://doi.org/10.1186/1471-2407-8-174
  6. Dweep H, Gretz N (2015). miRWalk2. 0: a comprehensive atlas of microRNA-target interactions. Nat Methods, 12, 697. https://doi.org/10.1038/nmeth.3485
  7. Evans WE, McLeod HL (2003). Pharmacogenomics-drug disposition, drug targets, and side effects. New Engl J Med, 348, 538-49. https://doi.org/10.1056/NEJMra020526
  8. Feliciano A, Castellvi J, Artero-Castro A, et al (2013). miR-125b acts as a tumor suppressor in breast tumorigenesis via its novel direct targets ENPEP, CK2-${\alpha}$, CCNJ, and MEGF9. PloS One, 8, 76247. https://doi.org/10.1371/journal.pone.0076247
  9. Bruno AE, Li L, Kalabus JL, et al (2012). miRdSNP: a database of disease-associated SNPs and microRNA target sites on 3’UTRs of human genes. BMC Genomics, 13, 44. https://doi.org/10.1186/1471-2164-13-44
  10. Cai J, Guan H, Fang L, et al (2013). MicroRNA-374a activates Wnt/${\beta}$-catenin signaling to promote breast cancer metastasis. J Clin Invest, 123, 566-79.
  11. Ferlay J, Soerjomataram I, Ervik M, et al (2013). GLOBOCAN 2012 v1. 0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base; International Agency for Research on Cancer.
  12. Honkakoski P, Negishi M (2000). Regulation of cytochrome P450 (CYP) genes by nuclear receptors. Biochem J, 347, 321-37. https://doi.org/10.1042/bj3470321
  13. Hughes TA (2006). Regulation of gene expression by alternative untranslated regions. Trends Genet, 22, 119-22. https://doi.org/10.1016/j.tig.2006.01.001
  14. Janssen EA, Slewa A, Gudlaugsson E, et al (2010). Biologic profiling of lymph node negative breast cancers by means of microRNA expression. Mod Pathol, 23, 1567-76. https://doi.org/10.1038/modpathol.2010.177
  15. Karagiannis GS, Weile J, Bader GD, Minta J (2013). Integrative pathway dissection of molecular mechanisms of moxLDLinduced vascular smooth muscle phenotype transformation. BMC Cardiovasc Disord, 13, 4. https://doi.org/10.1186/1471-2261-13-4
  16. Kotta-Loizou I, Patsouris E, Theocharis S (2013). Pregnane X receptor polymorphisms associated with human diseases. Expert opin Ther Targets, 17, 1167-77. https://doi.org/10.1517/14728222.2013.823403
  17. Lal S, Mahajan A, Ning Chen W, Chowbay B (2010). Pharmacogenetics of target genes across doxorubicin disposition pathway: a review. Curr Drug Metab, 11, 115-28. https://doi.org/10.2174/138920010791110890
  18. Lee YM, Lee JY, Ho CC, et al (2011). miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells. Breast Cancer Res, 13, 116. https://doi.org/10.1186/bcr3059
  19. Li N, Yang L, Wang H, et al (2015). miR-130a and miR-374a function as novel regulators of cisplatin resistance in human ovarian cancer a2780 cells. PloS One, 10, 128886.
  20. Lin Y, Liu AY, Fan C, et al (2015). MicroRNA-33b inhibits breast cancer metastasis by targeting HMGA2, SALL4 and Twist1. Sci Rep, 5, 9995. https://doi.org/10.1038/srep09995
  21. Liu C, Zhang F, Li T, et al (2012). MirSNP, a database of polymorphisms altering miRNA target sites, identifies miRNA-related SNPs in GWAS SNPs and eQTLs. BMC Genomics, 13, 661. https://doi.org/10.1186/1471-2164-13-661
  22. Masuyama H, Nakatsukasa H, Takamoto N, Hiramatsu Y (2007). Down-regulation of pregnane X receptor contributes to cell growth inhibition and apoptosis by anticancer agents in endometrial cancer cells. Mol Pharmacol, 72, 1045-53. https://doi.org/10.1124/mol.107.037937
  23. Nilsson S, Allred C, Howell A, Landberg G (2011). Stromal and epithelial microRNA signatures of early breast lesions linked to cancer progression. Cancer Res, 71, 3993. https://doi.org/10.1158/1538-7445.AM2011-3993
  24. Oleson L, von Moltke LL, Greenblatt DJ, Court MH (2010). Identification of polymorphisms in the 3'-untranslated region of the human pregnane X receptor (PXR) gene associated with variability in cytochrome P450 3A (CYP3A) metabolism. Xenobiotica, 40, 146-62. https://doi.org/10.3109/00498250903420243
  25. Omran A, Elimam D, Webster KA, Shehadeh LA, Yin F (2013). MicroRNAs: a new piece in the paediatric cardiovascular disease puzzle. Cardiol Young, 23, 642-55. https://doi.org/10.1017/S1047951113000048
  26. Pondugula SR, Mani S (2013). Pregnane xenobiotic receptor in cancer pathogenesis and therapeutic response. Cancer Lett, 328, 1-9. https://doi.org/10.1016/j.canlet.2012.08.030
  27. Qiao EQ, Yang HJ (2014). Effect of pregnane X receptor expression on drug resistance in breast cancer. Oncol Lett, 7, 1191-96. https://doi.org/10.3892/ol.2014.1817
  28. Schlitt A, Jordan K, Vordermark D, et al (2014). Cardiotoxicity and oncological treatments. Dtsch Arztebl Int, 111, 161-8.
  29. Singal PK, Iliskovic N (1998). Doxorubicin-induced cardiomyopathy. N Engl J Med, 339, 900-5. https://doi.org/10.1056/NEJM199809243391307
  30. Swart M, Dandara C (2013). Genetic variation in the 3'-UTR of CYP1A2, CYP2B6, CYP2D6, CYP3A4, NR1I2, and UGT2B7: potential effects on regulation by microRNA and pharmacogenomics relevance. Front Genet, 5, 167.
  31. Takagi S, Nakajima M, Mohri T, Yokoi T (2008). Posttranscriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4. J Biol Chem, 283, 9674-80. https://doi.org/10.1074/jbc.M709382200
  32. Van den Hoogen P, van den Akker F, Deddens JC, Sluijter JP (2015). Heart Failure in Chronic Myocarditis: A Role for microRNAs?. Curr Genomics, 16, 88-94. https://doi.org/10.2174/1389202916999150120153344
  33. Van Schooneveld E, Wildiers H, Vergote I, et al (2015). Dysregulation of microRNAs in breast cancer and their potential role as prognostic and predictive biomarkers in patient management. Breast Cancer Res, 17, 21. https://doi.org/10.1186/s13058-015-0526-y
  34. Vlachos IS, Kostoulas N, Vergoulis T, et al (2012). DIANA miRPath v. 2.0: investigating the combinatorial effect of microRNAs in pathways. Nucleic Acids Res, 40, 498-504. https://doi.org/10.1093/nar/gks494
  35. Wang Y, Gu X, Li Z, et al (2013). microRNA expression profiling in multidrug resistance of the 5‑Fu‑induced SGC‑7901 human gastric cancer cell line. Mol Med Rep, 7, 1506-10. https://doi.org/10.3892/mmr.2013.1384
  36. Wang J, Pei Y, Zhong Y, et al (2014). Altered serum microRNAs as novel diagnostic biomarkers for atypical coronary artery disease. PloS One, 9, 107012. https://doi.org/10.1371/journal.pone.0107012
  37. Wang JX, Zhang XJ, Feng C, et al (2015). MicroRNA-532-3p regulates mitochondrial fission through targeting apoptosis repressor with caspase recruitment domain in doxorubicin cardiotoxicity. Cell Death Dis, 6, 1677. https://doi.org/10.1038/cddis.2015.41
  38. Xing Y, Liu Z, Yang G, Gao D, Niu X (2015). MicroRNA expression profiles in rats with selenium deficiency and the possible role of the Wnt/${\beta}$‑catenin signaling pathway in cardiac dysfunction. Int J Mol Med, 35, 143-52. https://doi.org/10.3892/ijmm.2014.1976
  39. Zhang J, Kuehl P, Green ED, et al (2001). The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics, 11, 555-72. https://doi.org/10.1097/00008571-200110000-00003
  40. Zhang J, Wang Y, Zhen P, et al (2013). Genome-wide analysis of miRNA signature differentially expressed in doxorubicinresistant and parental human hepatocellular carcinoma cell lines. PLoS One, 8, 54111. https://doi.org/10.1371/journal.pone.0054111