Generic placeholder image

Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

Novel MicroRNA Binding Site SNPs and the Risk of Clear Cell Renal Cell Carcinoma (ccRCC): A Case-Control Study

Author(s): Irina R. Gilyazova, Narasimha M. Beeraka, Elizaveta A. Klimentova, Kirill V. Bulygin, Vladimir N. Nikolenko, Adel A. Izmailov, Gulshat R. Gilyazova, Valentin N. Pavlov, Elsa K. Khusnutdinova, Siva G. Somasundaram, Cecil E. Kirkland and Gjumrakch Aliev*

Volume 21, Issue 3, 2021

Published on: 20 November, 2020

Page: [203 - 212] Pages: 10

DOI: 10.2174/1568009620666201120151226

Price: $65


Background: Renal cell carcinoma represents 3% of all adult malignancies. MicroRNAs exhibit specific functions in various biological processes through their interaction with cellular mRNA involved in apoptosis and cell cycle control. Recent studies have reported the potential association of single-nucleotide polymorphisms (SNPs) in miRNA-binding sites of VHL-HIF1α pathway genes with renal cancer development and progression.

Objective: The objective of this study is to investigate the SNPs invoking an alteration in the nature of interaction with miRNA binding sites of VHL-HIF1α pathway genes.

Methods: Total 450 cases of histologically and clinically verified ccRCC and 490 controls were included in our study. Genotyping was performed using a TaqMan PCR allelic discrimination method. Kaplan-Meier method of statistical analysis was implemented to analyze the overall patient survival rate.

Results: Polymorphism rs10491534 in TSC1 gene was significantly associated with the risk of developing advanced ccRCC. Allele G of rs1642742 in VHL gene was significantly prevalent in ccRCC compared with the control group aged 55 and older (OR = 1.5566; CI [1.1532-2.1019]). Results from the dominant model combining individuals with AG or AA genotype showed that the A allele bearers of CDCP1 rs6773576 exhibited a higher risk of death compared to GG carriers (HR 3.93, 95% CI 1.76-17.21, log-rank P = 0.0033).

Conclusion: The present study delineated the association of miRNA binding site variants in VHL- HIF1α pathway genes with the ccRCC risk, which may affect the clinical outcomes.

Keywords: Renal cell carcinoma, miRNA, VHL-HIF1α pathway, polymorphism, epigenetics.

Graphical Abstract
Escudier, B.; Porta, C.; Schmidinger, M.; Rioux-Leclercq, N.; Bex, A.; Khoo, V.; Gruenvald, V.; Horwich, A. ESMO Guidelines Committee. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol., 2016, 27(Suppl. 5), v58-v68.
[] [PMID: 27664262]
Vasudev, N.S.; Selby, P.J.; Banks, R.E. Renal cancer biomarkers: the promise of personalized care. BMC Med., 2012, 10, 112.
[] [PMID: 23016578]
Cairns, P. Renal cell carcinoma. Cancer Biomark., 2010, 9(1-6), 461-473.
[] [PMID: 22112490]
Baylin, S.B.; Jones, P.A. Epigenetic determinants of cancer. Cold Spring Harb. Perspect. Biol., 2016, 8(9)
[] [PMID: 27194046]
Cora’, D.; Re, A.; Caselle, M.; Bussolino, F. MicroRNA-mediated regulatory circuits: outlook and perspectives. Phys. Biol., 2017, 14(4), 045001.
[] [PMID: 28586314]
Expósito-Villén, A.; E Aránega, A.; Franco, D. Functional role of non-coding RNAs during epithelial-to-mesenchymal transition. Noncoding RNA, 2018, 4(2), 14.
[] [PMID: 29843425]
Goradel, N.H.; Mohammadi, N.; Haghi-Aminjan, H.; Farhood, B.; Negahdari, B.; Sahebkar, A. Regulation of tumor angiogenesis by microRNAs: State of the art. J. Cell. Physiol., 2019, 234(2), 1099-1110.
[] [PMID: 30070704]
Kashyap, D.; Tuli, H.S.; Garg, V.K.; Goel, N.; Bishayee, A. Oncogenic and tumor-suppressive roles of MicroRNAs with special reference to apoptosis: molecular mechanisms and therapeutic potential. Mol. Diagn. Ther., 2018, 22(2), 179-201.
[] [PMID: 29388067]
Li, M.; Wang, Y.; Song, Y.; Bu, R.; Yin, B.; Fei, X.; Guo, Q.; Wu, B. MicroRNAs in renal cell carcinoma: a systematic review of clinical implications (Review). Oncol. Rep., 2015, 33(4), 1571-1578.
[] [PMID: 25682771]
He, Y.H.; Chen, C.; Shi, Z. The biological roles and clinical implications of microRNAs in clear cell renal cell carcinoma. J. Cell. Physiol., 2018, 233(6), 4458-4465.
[] [PMID: 29215721]
Braga, E.A.; Fridman, M.V.; Loginov, V.I.; Dmitriev, A.A.; Morozov, S.G. Molecular mechanisms in clear cell renal cell carcinoma: role of miRNAs and hypermethylated miRNA genes in crucial oncogenic pathways and processes. Front. Genet., 2019, 10, 320.
[] [PMID: 31110513]
Wei, H.; Ke, H.L.; Lin, J.; Shete, S.; Wood, C.G.; Hildebrandt, M.A. MicroRNA target site polymorphisms in the VHL-HIF1α pathway predict renal cell carcinoma risk. Mol. Carcinog., 2014, 53(1), 1-7.
[] [PMID: 22517515]
Haase, V.H. The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. Kidney Int., 2006, 69(8), 1302-1307.
[] [PMID: 16531988]
Ding, L; Jiang, Z; Chen, Q; Qin, R; Fang, Y; Li, H. A functional variant at miR-520a binding site in PIK3CA alters susceptibility to colorectal cancer in a Chinese Han population. BioMed research international, 2015.
Krishnamachary, B.; Zagzag, D.; Nagasawa, H.; Rainey, K.; Okuyama, H.; Baek, J.H.; Semenza, G.L. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res., 2006, 66(5), 2725-2731.
[] [PMID: 16510593]
Ogasa, M.Y.; Yazaki, K.; Utsumi, Y.; Miki, N.H.; Fukuda, K. Short-time xylem tension relaxation prevents vessel refilling and alleviates cryo-fixation artifacts in diffuse-porous Carpinus tschonoskii and Cercidiphyllum japonicum. Tree Physiol., 2019, 39(10), 1685-1695.
[] [PMID: 31222295]
Gunaratnam, L.; Morley, M.; Franovic, A.; de Paulsen, N.; Mekhail, K.; Parolin, D.A.; Nakamura, E.; Lorimer, I.A.; Lee, S. Hypoxia inducible factor activates the transforming growth factor-α/epidermal growth factor receptor growth stimulatory pathway in VHL(-/-) renal cell carcinoma cells. J. Biol. Chem., 2003, 278(45), 44966-44974.
[] [PMID: 12944410]
Li, D.H.; Whitmore, J.B.; Guo, W.; Ji, Y. Toxicity and efficacy probability interval design for phase I adoptive cell therapy dose-finding clinical trials. Clin. Cancer Res., 2017, 23(1), 13-20.
[] [PMID: 27742793]
Ellinger, J.; Gevensleben, H.; Müller, S.C.; Dietrich, D. The emerging role of non-coding circulating RNA as a biomarker in renal cell carcinoma. Expert Rev. Mol. Diagn., 2016, 16(10), 1059-1065.
[] [PMID: 27649770]
Croce, C.M. Causes and consequences of microRNA dysregulation in cancer. Nat. Rev. Genet., 2009, 10(10), 704-714.
[] [PMID: 19763153]
Robins, H.; Press, W.H. Human microRNAs target a functionally distinct population of genes with AT-rich 3′ UTRs. Proc. Natl. Acad. Sci. USA, 2005, 102(43), 15557-15562.
[] [PMID: 16230613]
Chalupová, L.; Zako vs ka, A.; Adamcova, K. Development of a novel enzyme-linked immunosorbent assay (ELISA) for measurement of serum CTRP1: a pilot study: measurement of serum CTRP1 in healthy donors and patients with metabolic syndrome. Clin. Biochem., 2013, 46(1-2), 73-78.
[] [PMID: 23000311]
Horikawa, Y.; Wood, C.G.; Yang, H.; Zhao, H.; Ye, Y.; Gu, J.; Lin, J.; Habuchi, T.; Wu, X. Single nucleotide polymorphisms of microRNA machinery genes modify the risk of renal cell carcinoma. Clin. Cancer Res., 2008, 14(23), 7956-7962.
[] [PMID: 19047128]
Lin, J.; Horikawa, Y.; Tamboli, P.; Clague, J.; Wood, C.G.; Wu, X. Genetic variations in microRNA-related genes are associated with survival and recurrence in patients with renal cell carcinoma. Carcinogenesis, 2010, 31(10), 1805-1812.
[] [PMID: 20732906]
Chow, T.F.; Youssef, Y.M.; Lianidou, E.; Romaschin, A.D.; Honey, R.J.; Stewart, R.; Pace, K.T.; Yousef, G.M. Differential expression profiling of microRNAs and their potential involvement in renal cell carcinoma pathogenesis. Clin. Biochem., 2010, 43(1-2), 150-158.
[] [PMID: 19646430]
Zhong, T.; Xu, F.; Xu, J.; Liu, L.; Chen, Y. Aldo-keto reductase 1C3 (AKR1C3) is associated with the doxorubicin resistance in human breast cancer via PTEN loss. Biomed. Pharmacother., 2015, 69, 317-325.
[] [PMID: 25661377]
Liu, H.; Gao, F.; Dahlstrom, K.R.; Li, G.; Sturgis, E.M.; Zevallos, J.P.; Wei, Q.; Liu, Z. A variant at a potentially functional microRNA-binding site in BRIP1 was associated with risk of squamous cell carcinoma of the head and neck. Tumour Biol., 2016, 37(6), 8057-8066.
[] [PMID: 26711789]
van Houwelingen, K.P.; van Dijk, B.A.; Hulsbergen-van de Kaa, C.A.; Schouten, L.J.; Gorissen, H.J.; Schalken, J.A.; van den Brandt, P.A.; Oosterwijk, E. Prevalence of von Hippel-Lindau gene mutations in sporadic renal cell carcinoma: results from The Netherlands cohort study. BMC Cancer, 2005, 5, 57.
[] [PMID: 15932632]
Groulx, I.; Lee, S. Oxygen-dependent ubiquitination and degradation of hypoxia-inducible factor requires nuclear-cytoplasmic trafficking of the von Hippel-Lindau tumor suppressor protein. Mol. Cell. Biol., 2002, 22(15), 5319-5336.
[] [PMID: 12101228]
Rathmell, W.K.; Chen, S. VHL inactivation in renal cell carcinoma: implications for diagnosis, prognosis and treatment. Expert Rev. Anticancer Ther., 2008, 8(1), 63-73.
[] [PMID: 18095884]
Mehta, M.S.; Vazquez, A.; Kulkarni, D.A.; Kerrigan, J.E.; Atwal, G.; Metsugi, S.; Toppmeyer, D.L.; Levine, A.J.; Hirshfield, K.M. Polymorphic variants in TSC1 and TSC2 and their association with breast cancer phenotypes. Breast Cancer Res. Treat., 2011, 125(3), 861-868.
[] [PMID: 20658316]
Hildebrandt, M.A.; Lippman, S.M.; Etzel, C.J.; Kim, E.; Lee, J.J.; Khuri, F.R.; Spitz, M.R.; Lotan, R.; Hong, W.K.; Wu, X. Genetic variants in the PI3K/PTEN/AKT/mTOR pathway predict head and neck cancer patient second primary tumor/recurrence risk and response to retinoid chemoprevention. Clin. Cancer Res., 2012, 18(13), 3705-3713.
[] [PMID: 22577058]
Song, P.; Wang, W.; Tao, G.; Chu, H.; Wang, M.; Wu, D.; Tong, N.; Gong, W.; Zhou, J.; Zhang, Z.; Wang, B.; Zhu, H.; Zhao, Q. A miR-29c binding site genetic variant in the 3′-untranslated region of LAMTOR3 gene is associated with gastric cancer risk. Biomed. Pharmacother., 2015, 69, 70-75.
[] [PMID: 25661340]
Ohlsson, C.; Wallaschofski, H.; Lunetta, K.L.; Stolk, L.; Perry, J.R.; Koster, A.; Petersen, A-K.; Eriksson, J.; Lehtimäki, T.; Huhtaniemi, I.T.; Hammond, G.L.; Maggio, M.; Coviello, A.D.; Ferrucci, L.; Heier, M.; Hofman, A.; Holliday, K.L.; Jansson, J.O.; Kähönen, M.; Karasik, D.; Karlsson, M.K.; Kiel, D.P.; Liu, Y.; Ljunggren, O.; Lorentzon, M.; Lyytikäinen, L.P.; Meitinger, T.; Mellström, D.; Melzer, D.; Miljkovic, I.; Nauck, M.; Nilsson, M.; Penninx, B.; Pye, S.R.; Vasan, R.S.; Reincke, M.; Rivadeneira, F.; Tajar, A.; Teumer, A.; Uitterlinden, A.G.; Ulloor, J.; Viikari, J.; Völker, U.; Völzke, H.; Wichmann, H.E.; Wu, T.S.; Zhuang, W.V.; Ziv, E.; Wu, F.C.; Raitakari, O.; Eriksson, A.; Bidlingmaier, M.; Harris, T.B.; Murray, A.; de Jong, F.H.; Murabito, J.M.; Bhasin, S.; Vandenput, L.; Haring, R. EMAS Study Group. Genetic determinants of serum testosterone concentrations in men. PLoS Genet., 2011, 7(10)
[] [PMID: 21998597]
Wang, W-C.; Tsou, M-H.; Chen, H-J.; Hsu, W-F.; Lai, Y-C. Two single nucleotide polymorphisms in the von Hippel-Lindau tumor suppressor gene in Taiwanese with renal cell carcinoma. BMC Res. Notes, 2014, 7, 638.
[] [PMID: 25217002]
Znaor, A.; Lortet-Tieulent, J.; Laversanne, M.; Jemal, A.; Bray, F. International variations and trends in renal cell carcinoma incidence and mortality. Eur. Urol., 2015, 67(3), 519-530.
[] [PMID: 25449206]
He, Y.; Wu, A.C.; Harrington, B.S.; Davies, C.M.; Wallace, S.J.; Adams, M.N.; Palmer, J.S.; Roche, D.K.; Hollier, B.G.; Westbrook, T.F.; Hamidi, H.; Konecny, G.E.; Winterhoff, B.; Chetty, N.P.; Crandon, A.J.; Oliveira, N.B.; Shannon, C.M.; Tinker, A.V.; Gilks, C.B.; Coward, J.I.; Lumley, J.W.; Perrin, L.C.; Armes, J.E.; Hooper, J.D. Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance. Oncogene, 2016, 35(4), 468-478.
[] [PMID: 25893298]
Razorenova, O.V.; Finger, E.C.; Colavitti, R.; Chernikova, S.B.; Boiko, A.D.; Chan, C.K.; Krieg, A.; Bedogni, B.; LaGory, E.; Weissman, I.L.; Broome-Powell, M.; Giaccia, A.J. VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration. Proc. Natl. Acad. Sci. USA, 2011, 108(5), 1931-1936.
[] [PMID: 21233420]
Jeys, L.M.; Grimer, R.J.; Carter, S.R.; Tillman, R.M.; Abudu, A. Post operative infection and increased survival in osteosarcoma patients: are they associated? Ann. Surg. Oncol., 2007, 14(10), 2887-2895.
[] [PMID: 17653803]
Emerling, B.M.; Benes, C.H.; Poulogiannis, G.; Bell, E.L.; Courtney, K.; Liu, H.; Choo-Wing, R.; Bellinger, G.; Tsukazawa, K.S.; Brown, V.; Signoretti, S.; Soltoff, S.P.; Cantley, L.C. Identification of CDCP1 as a hypoxia-inducible factor 2α (HIF-2α) target gene that is associated with survival in clear cell renal cell carcinoma patients. Proc. Natl. Acad. Sci. USA, 2013, 110(9), 3483-3488.
[] [PMID: 23378636]
Chou, C-T.; Li, Y-J.; Chang, C-C.; Yang, C-N.; Li, P-S.; Jeng, Y-M.; Chen, S-T.; Kuo, M-L.; Lin, I-C.; Lin, B-R. Prognostic significance of CDCP1 expression in colorectal cancer and effect of its inhibition on invasion and migration. Ann. Surg. Oncol., 2015, 22(13), 4335-4343.
[] [PMID: 25820997]
Greene, C.J.; Attwood, K.; Sharma, N.J.; Gross, K.W.; Smith, G.J.; Xu, B.; Kauffman, E.C. Transferrin receptor 1 upregulation in primary tumor and downregulation in benign kidney is associated with progression and mortality in renal cell carcinoma patients. Oncotarget, 2017, 8(63), 107052-107075.
[] [PMID: 29291011]
Qian, W.; Kong, X.; Zhang, T.; Wang, D.; Song, J.; Li, Y.; Li, X.; Geng, H.; Min, J.; Kong, Q.; Liu, J.; Liu, Z.; Wang, D.; Zhang, Z.; Yu, D.; Zhong, C. Cigarette smoke stimulates the stemness of renal cancer stem cells via Sonic Hedgehog pathway. Oncogenesis, 2018, 7(3), 24.
[] [PMID: 29540668]
Hunt, J.D.; van der Hel, O.L.; McMillan, G.P.; Boffetta, P.; Brennan, P. Renal cell carcinoma in relation to cigarette smoking: meta-analysis of 24 studies. Int. J. Cancer, 2005, 114(1), 101-108.
[] [PMID: 15523697]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy