Abstract
Purpose
To investigate associations between genetic variants involved in microRNA networks (microRNA biogenesis, microRNA and microRNA binding sites) and risk of gastric cancer.
Methods
We genotyped 19 SNPs of the microRNA-related genes in a case–control study of 311 gastric cancers and 425 cancer-free controls in a Chinese Han population.
Results
We found that two of the SNPs were significantly associated with gastric cancer. Inhibitory effect of minor allele T of rs2071504 SNP within the exon of POLR2A gene was significantly associated with gastric carcinogenesis (p = 0.033, aOR = 0.742, 95%CI = 0.564–0.977) and the SNP rs895819 in the miR-27a gene with the minor allele C presented significantly reduced risk to gastric cancer (p = 0.037, aOR = 0.771, 95%CI = 0.604–0.985). Further stratified analysis with regard to clinical pathological parameters of the patients indicated that the SNP rs2071504 was associated with lymph node metastasis (p = 0.021, aOR = 0.529, 95%CI = 0.307–0.910) and TMN stage (p = 0.021, aOR = 0.532, 95%CI = 0.311–0.908), respectively.
Conclusions
Our findings provided evidence that the SNP rs2071504 in the exon of POLR2A gene would not only confer a decreased risk of gastric cancer, but also influence lymph node metastasis and TMN stage of gastric cancer in the Chinese population.
Similar content being viewed by others
References
Ambros V (2003) MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell 113(6):673–676
Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP (2008) The impact of microRNAs on protein output. Nature 455(7209):64–71. doi:10.1038/nature07242
Barrera LO, Li Z, Smith AD, Arden KC, Cavenee WK, Zhang MQ, Green RD, Ren B (2008) Genome-wide mapping and analysis of active promoters in mouse embryonic stem cells and adult organs. Genome Res 18(1):46–59. doi:10.1101/gr.6654808
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297
Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233. doi:10.1016/j.cell.2009.01.002
Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM (2003) bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113(1):25–36
Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM (2005) A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 353(17):1793–1801. doi:10.1056/NEJMoa050995
Clague J, Lippman SM, Yang H, Hildebrandt MA, Ye Y, Lee JJ, Wu X (2010) Genetic variation in MicroRNA genes and risk of oral premalignant lesions. Mol Carcinog 49(2):183–189. doi:10.1002/mc.20588
Crew KD, Neugut AI (2006) Epidemiology of gastric cancer. World J Gastroenterol 12(3):354–362
Duan R, Pak C, Jin P (2007) Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet 16(9):1124–1131. doi:10.1093/hmg/ddm062
Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3(6):453–458. doi:10.1038/nrc1098
Hoffman AE, Zheng T, Yi C, Leaderer D, Weidhaas J, Slack F, Zhang Y, Paranjape T, Zhu Y (2009) microRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis. Cancer Res 69(14):5970–5977. doi:10.1158/0008-5472.CAN-09-0236
Kumar MS, Erkeland SJ, Pester RE, Chen CY, Ebert MS, Sharp PA, Jacks T (2008) Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci USA 105(10):3903–3908. doi:10.1073/pnas.0712321105
Landi D, Gemignani F, Barale R, Landi S (2008) A catalog of polymorphisms falling in microRNA-binding regions of cancer genes. DNA Cell Biol 27(1):35–43. doi:10.1089/dna.2007.0650
Langley RR, Fidler IJ (2007) Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev 28(3):297–321. doi:10.1210/er.2006-0027
Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120(1):15–20. doi:10.1016/j.cell.2004.12.035
Liang S, He L, Zhao X, Miao Y, Gu Y, Guo C, Xue Z, Dou W, Hu F, Wu K, Nie Y, Fan D (2011) MicroRNA let-7f inhibits tumor invasion and metastasis by targeting MYH9 in human gastric cancer. PLoS One 6(4):e18409. doi:10.1371/journal.pone.0018409
Liu T, Tang H, Lang Y, Liu M, Li X (2009) MicroRNA-27a functions as an oncogene in gastric adenocarcinoma by targeting prohibitin. Cancer Lett 273(2):233–242. doi:10.1016/j.canlet.2008.08.003
Ma Y, Yu S, Zhao W, Lu Z, Chen J (2010) miR-27a regulates the growth, colony formation and migration of pancreatic cancer cells by targeting Sprouty2. Cancer Lett 298(2):150–158. doi:10.1016/j.canlet.2010.06.012
Mishra PJ, Bertino JR (2009) MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine. Pharmacogenomics 10(3):399–416. doi:10.2217/14622416.10.3.399
Peng S, Kuang Z, Sheng C, Zhang Y, Xu H, Cheng Q (2010) Association of microRNA-196a-2 gene polymorphism with gastric cancer risk in a Chinese population. Dig Dis Sci 55(8):2288–2293. doi:10.1007/s10620-009-1007-x
Portal MM (2011) MicroRNA-27a regulates basal transcription by targeting the p44 subunit of general transcription factor IIH. Proc Natl Acad Sci USA 108(21):8686–8691. doi:10.1073/pnas.1014018108
Raveche ES, Salerno E, Scaglione BJ, Manohar V, Abbasi F, Lin YC, Fredrickson T, Landgraf P, Ramachandra S, Huppi K, Toro JR, Zenger VE, Metcalf RA, Marti GE (2007) Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice. Blood 109(12):5079–5086. doi:10.1182/blood-2007-02-071225
Reshmi G, Surya R, Jissa VT, Babu PS, Preethi NR, Santhi WS, Jayaprakash PG, Pillai MR (2011) C-T variant in a miRNA target site of BCL2 is associated with increased risk of human papilloma virus related cervical cancer-An in silico approach. Genomics 98(3):189–193. doi:10.1016/j.ygeno.2011.06.005
Ryan BM, Robles AI, Harris CC (2010) Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer 10(6):389–402. doi:10.1038/nrc2867
Saetrom P, Biesinger J, Li SM, Smith D, Thomas LF, Majzoub K, Rivas GE, Alluin J, Rossi JJ, Krontiris TG, Weitzel J, Daly MB, Benson AB, Kirkwood JM, O’Dwyer PJ, Sutphen R, Stewart JA, Johnson D, Larson GP (2009) A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis. Cancer Res 69(18):7459–7465. doi:10.1158/0008-5472.CAN-09-1201
Smith PJ, Zhang C, Wang J, Chew SL, Zhang MQ, Krainer AR (2006) An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers. Hum Mol Genet 15(16):2490–2508. doi:10.1093/hmg/ddl171
Sun Q, Gu H, Zeng Y, Xia Y, Wang Y, Jing Y, Yang L, Wang B (2010) Hsa-mir-27a genetic variant contributes to gastric cancer susceptibility through affecting miR-27a and target gene expression. Cancer Sci 101(10):2241–2247. doi:10.1111/j.1349-7006.2010.01667.x
Tian T, Shu Y, Chen J, Hu Z, Xu L, Jin G, Liang J, Liu P, Zhou X, Miao R, Ma H, Chen Y, Shen H (2009) A functional genetic variant in microRNA-196a2 is associated with increased susceptibility of lung cancer in Chinese. Cancer Epidemiol Biomarkers Prev 18(4):1183–1187. doi:10.1158/1055-9965.EPI-08-0814
Tseng CW, Lin CC, Chen CN, Huang HC, Juan HF (2011) Integrative network analysis reveals active microRNAs and their functions in gastric cancer. BMC Syst Biol 5:99. doi:10.1186/1752-0509-5-99
Xu Y, Zhao F, Wang Z, Song Y, Luo Y, Zhang X, Jiang L, Sun Z, Miao Z, Xu H (2011) MicroRNA-335 acts as a metastasis suppressor in gastric cancer by targeting Bcl-w and specificity protein 1. Oncogene. doi:10.1038/onc.2011.340
Yang D, Wang S, Brooks C, Dong Z, Schoenlein PV, Kumar V, Ouyang X, Xiong H, Lahat G, Hayes-Jordan A, Lazar A, Pollock R, Lev D, Liu K (2009) IFN regulatory factor 8 sensitizes soft tissue sarcoma cells to death receptor-initiated apoptosis via repression of FLICE-like protein expression. Cancer Res 69(3):1080–1088. doi:10.1158/0008-5472.CAN-08-2520
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhou, Y., Du, WD., Chen, G. et al. Association analysis of genetic variants in microRNA networks and gastric cancer risk in a Chinese Han population. J Cancer Res Clin Oncol 138, 939–945 (2012). https://doi.org/10.1007/s00432-012-1164-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-012-1164-8