Analysis of miRNA-Mediated ceRNAs In The Pathogenesis of Renal Cell Carcinoma: An In Silico Approach

Year 2020, Volume: 7 Issue: 3, 223 - 238, 30.09.2020

Orcun Avsar

https://doi.org/10.17350/HJSE19030000192

Abstract

R ments in surgical and other novel treatment strategies. Competing endogenous RNAs ceRNAs are considered as significant post-transcriptional regulators that modulate gene expression via miRNA-mediated regulatory networks. Furthermore, it has been demon- strated that ceRNAs have remarkable functions in the pathogenesis of cancers by modulat- ing the expression of oncogenes or tumor-suppressive genes. The aim of this study was to define novel molecular biomarkers for RCC via in silico analysis. Seven miRNAs which have clinical significance for renal cell carcinomas were exported through miRTarBase database. 1001 genes which are targeted by these 7 miRNAs simultaneously were deter- mined by ComiR database. The genes with T-UCR in their exonic regions and which have the potential ceRNA activities were extracted. Gene expression differences between RCC and normal kidney tissues according to the renal cell carcinoma-associated ceRNAs involving T-UCR were identified by GEPIA. The statistical analysis of the relationship between NRXN3 and PTBP2 genes with RCC was determined by Spearman correlation test. NRXN3 and PTBP2 were found to be significantly associated with RCC p=0.0057; R=-0.29 . The current study demonstrates for the first time that PTBP2 gene is associated with renal cell carcinoma. The results of in silico analysis suppose that PTBP2 gene may have potential tumor suppressor role in RCC and NRXN3 gene may have potential onco- genic activity in RCC. Further in vitro and in vivo studies are required in order to clarify tumor suppressor role of PTBP2 and oncogenic activity of NRXN3 in RCC

Keywords

miRNA, ceRNA, T-UCR, Renal cell carcinoma, PTBP2, NRXN3

References

• 1. Okoń K. Pathology of renal tumors in adults. Molecular biology, histopathological diagnosis and prognosis. Polish Journal of Pathology 59 (2008) 129-76.
• 2. Choueiri TK, Je Y, Cho E. Analgesic use and the risk of kidney cancer: a meta-analysis of epidemiologic studies. International Journal of Cancer 134 (2014) 384-96.
• 3. Macleod LC, Hotaling JM, Wright JL, Davenport MT, Gore JL, Harper J, White E. Risk factors for renal cell carcinoma in the VITAL study. The Journal of Urology 190 (2013) 1657-61.
• 4. Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumours of the urinary system and male genital organs- part A: Renal, penile, and testicular tumours. European Urology 70 (2016) 93-105.
• 5. Moch H, Humphrey PA, Ulbright TM, Reuter VE. WHO classification of tumours of the urinary system and male genital organs. Fourth Edition. 2016.
• 6. Goyal R, Gersbach E, Yang XJ, Rohan SM. Differential diagnosis of renal tumors with clear cytoplasm. Archives of Pathology and Laboratory Medicine 137 (2013) 467-480.
• 7. Huang Y, Shen XJ, Zou Q, Wang SP, Tang SM, Zhang GZ. Biololgical functions of microRNAs: a review. Journal of Physiology and Biochemistry 67 (2011) 129-139.
• 8. Rama K, Srinivasa Rao PVLN, Bitla AR. MicroRNAs in health and disease. Journal of Clinical and Scientific Research. 6 (2017) 25-34.
• 9. Qi X, Zhang DH, Wu N, Xiao JH, Wang X, Ma W. ceRNA in cancer: possible functions and clinical implications. Journal of Medical Genetics 0 (2015) 1-9.
• 10. Kartha RV, Subramanian S. Competing endogenous RNAs (ceRNAs): new entrants to the intricacies of gene regulation. Frontiers in Genetics. 5 (2014) 8.
• 11. Zambalde EP, Mathias C, Rodrigues AC, de Souza Fonseca Ribeiro EM, Gradia DF, Calin GA, de Oliveira JC. Highlighting transcribed ultraconserved regions in human diseases. WIRES RNA 11 (2020) e1567.
• 12. Mudgapalli N, Shaw BP, Chava S, Challagundla KB. The transcribed-ultra conserved regions: Novel non-coding RNA players in neuroblastoma progression. Non-coding RNA 5 (2019) 39.
• 13. Chou CH, Shrestha S, Yang CD, Chang NW, Lin YL, Liao KW, Huang WC, Sun TH, Tu SJ, Lee WH, Chiew MY, Tai CS, Wei TY, Tsai TR, Huang HT, Wang CY, Wu HY, Ho SY, Chen PR, Chuang CH, Hsieh PJ, Wu YS, Chen WL, Li MJ, Wu YC, Huang XY, Ng FL, Buddhakosai W, Huang PC, Lan KC, Huang CY, Weng SL, Cheng YN, Liang C, Hsu WL, Huang HD. miTarBase update 2018: a rosource for experimentally validated microRNA-target interactions. Nucleic Acids Research 46 (2018) D296-D302.
• 14. Davis JA, Saunders SJ, Mann M, Backofen R. Combinatorial ensemble miRNA target prediction of co-regulation networks with non-prediction data. Nucleic Acids Research 45 (2017) 8745-8757.
• 15. Bejerano G, Pheasant M, Makunin I, Stephen S, Kent WJ, Mattick JS, Haussler D. Ultraconserved elements in the human genome. Science 304 (2004) 1321-5.
• 16. Thang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analysis. Nucleic Acid Research 45 (2017) W98-W102.
• 17. Grange C, Brossa A, Bussolati B. Extracellular vesicles and carried miRNAs in the progression of renal cell carcinoma. International Journal of Molecular Sciences 20 (2019) 1832.
• 18. Sanchez-Gastaldo A, Kempf E, del Alba AG, Duran I. Systemic treatment of renal cell cancer: A comprehensive review. Cancer Treatments Review 60 (2017) 77-89.
• 19. Alaghehbandan R, Montiel DP, Luis AS, Hes O. Molecular genetics of renal cell tumors: A practical diagnostic approach. Cancers 12 (85) 1-24.
• 20. Li M, Wang Y, Song Y, Bu R, Yin B, Fei X, Guo Q, Wu B. MicroRNAs in renal cell carcinoma: A systemic review of clinical implications (Review). Oncology Reports 33 (2015) 1571-1578.
• 21. Sun HT, Cheng SX, Tu Y, Li XH, Zhang S. FoxQ1 promotes glioma cells proliferation and migration by regulating NRXN3 expression. PLoS ONE 8 (2013) e55693.
• 22. Hirohata H, Yanagawa T, Takaoka S, Uchida F, Shibuya Y, Miyabe S, Tabuchi K, Akagi Y, Hasegawa S, Sakai S, Takeuchi Y, Ishibashi-Kanno N, Yamagata K, Bukawa H. Synaptic-adhesion molecules neurexin 1 and neuroligin 1 as novel prognostic factors in oral squamous cell carcinoma. Journal of Dentistry and Dental Medicine 1 (2018) 111.
• 23. Xiang XJ, Deng J, Liu YW, Wan LY, Feng M, Chen J, Xiong JP. MiR1271 inhibits cell proliferation, invasion and EMT in gastric cancer by targeting FOXQ1. Cellular Physiology and Biochemistry 36 (2015) 1382-1394.
• 24. Licatalosi DD, Yano M, Fak JJ, Mele A, Grabinski SE, Zhang C, Darnell RB. Ptbp2 represses adult-specific splicing to regulate the generation of neuronal precursors in the embryonic brain. Genes and Development 26 (2012) 1626-1642.
• 25. Cheung HC, Hai T, Zhu W, Baggerly KA, Tsavachidis S, Krahe R, Cote GJ. Splicing factors PTBP1 and PTBP2 promote proliferation and migration of glioma cell lines. Brain (2009) 2277-88.
• 26. Ji Q, Zhang L, Liu X, Zhou L, Wang W, Han Z, et al. Long noncoding RNA MALAT1 promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2 complex. British Journal of Cancer 111 (2014) 736-748.
• 27. Lou S, Ji J, Cheng X, Ruan J, Li R, Guo Z. Oncogenic miR 132 sustains proliferation and self renewal potential by inhibition of polypyrimidine tract binding protein 2 in glioblastoma cells. Molecular Medicine Reports 16 (2017) 7221-8.
• 28. Jiang J, Chen X, Liu H, Shao J, Xie R, Gu P, et al. Polypyrimidine Tract-Binding Protein 1 promotes proliferation, migration and invasion in clear-cell renal cell carcinoma by regulating alternative splicing of PKM. American Journal of Cancer Research 7 (2017) 245-259.
• 29. Di Meo A, Saleeb R, Wala SJ, Khella HW, Ding Q, Zhai H, et al. A miRNA-based classification of renal cell carcinoma subtypes by PCR and in situ hybridization. Oncotarget 9 (2018) 2092-2104.
• 30. Ying G, Wu R, Xia M, Fei X, He QE, Zha C, et al. Identification of eight key miRNAs associated with renal cell carcinoma: A metaanalysis. Oncology Letters 16 (2018) 5847-5855.