Tumor Biology

, Volume 35, Issue 8, pp 7775–7780 | Cite as

Association between miR-146aG>C and miR-196a2C>T polymorphisms and the risk of hepatocellular carcinoma in a Chinese population

  • Bing Zhou
  • Liang-peng Dong
  • Xiao-yue Jing
  • Jin-song Li
  • Shu-juan Yang
  • Jun-ping Wang
  • Long-feng Zhao
Research Article


MicroRNAs have been demonstrated to have a role in susceptibility and prognosis of various types of human cancer. We investigated the association between polymorphisms in miR-146aG>C, miR-196a2C>T, and miR-499A>G and hepatocellular carcinoma (HCC) risk and interaction with HCC and hepatitis B virus (HBV) infection. Two hundred sixty-six cases with HCC and 281 health controls were enrolled in the present study. Genotyping of the miR-146aG>C, miR-196a2C>T, and miR-499A>G genotypes was conducted by duplex polymerase chain reaction with the confronting two-pair primer (PCR–RFLP). Subjects with miR-146a GG and G allele had an increased risk of HCC compared with the homozygote CC genotype. Similarly, HCC patients carrying microRNA (miRNA)-196a2 computed tomography, TT, and T allele significantly decreased the risk of HCC relative to the CC genotype. Stratified analysis indicated that miR-196a2C>T polymorphism was associated with reduced risk of HBV-related HCC, but not in hepatitis C virus- and nonviral-related HCC cases. In conclusion, miR-146aG>C and miR-196a2C>T polymorphism are associated with risk of HCC patients in China, especially in patients with HBV infection. SNPs in miRNA sequences can be used as a diagnostic biomarker for HCC.


MicroRNA Polymorphisms Hepatocellular carcinoma HBV 



We thank the First Affiliated Hospital of Xinxiang Medical University.

Conflicts of interest



  1. 1.
    [Internet] International Agency for Research on Cancer. Globocan 2008 in China. Accessed 1 Oct 2013
  2. 2.
    Yu MC, Yuan JM. Environmental factors and risk for hepatocellular carcinoma. Gastroenterology. 2004;127:S72–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gastroenterology. 2004;127:1372–80.PubMedCrossRefGoogle Scholar
  4. 4.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.PubMedCrossRefGoogle Scholar
  5. 5.
    Valencia-Sanchez MA, Liu J, Hannon GJ, et al. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006;20:515–24.PubMedCrossRefGoogle Scholar
  6. 6.
    Lim LP, Lau NC, Garrett-Engele P, Grimson A, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433(7027):769–73.PubMedCrossRefGoogle Scholar
  7. 7.
    Wilfred BR, Wang WX, Nelson PT. Energizing miRNA research: a review of the role of miRNAs in lipid metabolism, with a prediction that miR-103/107 regulates human metabolic pathways. Mol Genet Metab. 2007;91(3):209–17.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Pizzini S, Bisognin A, Mandruzzato S, Biasiolo M, Facciolli A, Perilli L, et al. Impact of microRNAs on regulatory networks and pathways in human colorectal carcinogenesis and development of metastasis. BMC Genomics. 2013;14(1):589.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Sung SY, Liao CH, Wu HP, Hsiao WC, Wu IH, Jinpu Y, et al. Loss of Let-7 microRNA upregulates IL-6 in bone marrow-derived mesenchymal stem cells triggering a reactive stromal response to prostate cancer. PLoS One. 2013;8(8):e71637.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Saito K, Inagaki K, Kamimoto T, Ito Y, Sugita T, Nakajo S, et al. MicroRNA-196a is a putative diagnostic biomarker and therapeutic target for laryngeal cancer. PLoS One. 2013;8(8):e71480.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    He B, Pan Y, Cho WC, Xu Y, Gu L, Nie Z, et al. The association between four genetic variants in microRNAs (rs11614913, rs2910164, rs3746444, rs2292832) and cancer risk: evidence from published studies. PLoS One. 2012;7(11):e49032.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Hu Z, Liang J, Wang Z, Tian T, et al. Common genetic variants in pre-microRNAs were associated with increased risk of breast cancer in Chinese women. Hum Mutat. 2009;30(1):79–84.PubMedCrossRefGoogle Scholar
  13. 13.
    Lee HC, Kim JG, Chae YS, Sohn SK, et al. Prognostic impact of microRNA-related gene polymorphisms on survival of patients with colorectal cancer. J Cancer Res Clin Oncol. 2010;136(7):1073–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Qi P, Dou TH, Geng L, Zhou FG, Gu X, Wang H, et al. Association of a variant in MIR 196A2 with susceptibility to hepatocellular carcinoma in male Chinese patients with chronic hepatitis B virus infection. Hum Immunol. 2010;71(6):621–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Li XD, Li ZG, Song XX, Liu CF. A variant in microRNA-196a2 is associated with susceptibility to hepatocellular carcinoma in Chinese patients with cirrhosis. Pathology. 2010;42(7):669–73.PubMedCrossRefGoogle Scholar
  16. 16.
    Xiang Y, Fan S, Cao J, Huang S, et al. Association of the microRNA-499 variants with susceptibility to hepatocellular carcinoma in a Chinese population. Mol Biol Rep. 2012;39(6):7019–23.PubMedCrossRefGoogle Scholar
  17. 17.
    Kim WH, Min KT, Jeon YJ, Kwon CI, et al. Association study of microRNA polymorphisms with hepatocellular carcinoma in Korean population. Gene. 2012;504(1):92–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Hu M, Zhao L, Hu S, Yang J. The association between two common polymorphisms in microRNAs and hepatocellular carcinoma risk in Asian population. PLoS One. 2013;8(2):e57012.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Zheng SQ, Li YX, Zhang Y, et al. MiR-101 regulates HSV-1 replication by targeting ATP5B. Antivir Res. 2011;89:219–26.PubMedCrossRefGoogle Scholar
  20. 20.
    Cui C, Griffiths A, Li G, et al. Prediction and identification of herpes simplex virus 1-encoded microRNAs. J Virol. 2006;80:5499–508.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Wu M, Jolicoeur N, Li Z, Zhang L, et al. Genetic variations of microRNAs in human cancer and their effects on the expression of miRNAs. Carcinogenesis. 2008;29(9):1710–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Xi JJ. MicroRNAs in Cancer. Cancer Treat Res. 2013;158:119–37.PubMedCrossRefGoogle Scholar
  23. 23.
    Tian T, Shu Y, Chen J, Hu Z, Xu L, Jin G, et al. A functional genetic variant in microRNA-196a2 is associated with increased susceptibility of lung cancer in Chinese. Cancer Epidemiol Biomarkers Prev. 2009;18(4):1183–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Wang S, Tao G, Wu D, Zhu H, Gao Y, Tan Y, et al. A functional polymorphism in MIR196A2 is associated with risk and prognosis of gastric cancer. Mol Carcinog. 2013;52 Suppl 1:87–95.CrossRefGoogle Scholar
  25. 25.
    Hezova R, Kovarikova A, Bienertova-Vasku J, Sachlova M, Redova M, Vasku A, et al. Evaluation of SNPs in miR-196-a2, miR-27a and miR-146a as risk factors of colorectal cancer. World J Gastroenterol. 2012;18(22):2827–31.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Zhang M, Jin M, Yu Y, Zhang S, Wu Y, Liu H, et al. Associations of miRNA polymorphisms and female physiological characteristics with breast cancer risk in Chinese population. Eur J Cancer Care (Engl). 2012;21(2):274–80.CrossRefGoogle Scholar
  27. 27.
    Han Y, Pu R, Han X, Zhao J, Zhang Y, Zhang Q, et al. Associations of pri-miR-34b/c and pre-miR-196a2 polymorphisms and their multiplicative interactions with hepatitis B virus mutations with hepatocellular carcinoma risk. PLoS One. 2013;8(3):e58564.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Akkız H, Bayram S, Bekar A, Akgöllü E, Ulger Y. A functional polymorphism in pre-microRNA-196a-2 contributes to the susceptibility of hepatocellular carcinoma in a Turkish population: a case–control study. J Viral Hepat. 2011;18(7):e399–407.PubMedCrossRefGoogle Scholar
  29. 29.
    Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR, de la Chapelle A. Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci U S A. 2008;105:7269–74.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Xu B, Feng NH, Li PC, Tao J, Wu D, Zhang ZD, et al. A functional polymorphism in Pre-miR-146a gene is associated with prostate cancer risk and mature miR-146a expression in vivo. Prostate. 2010;70:467–72.PubMedCrossRefGoogle Scholar
  31. 31.
    Zeng Y, Sun QM, Liu NN, Dong GH, Chen J, Yang L, et al. Correlation between pre-miR-146a C/G polymorphism and gastric cancer risk in Chinese population. World J Gastroenterol. 2010;16:3578–83.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Okubo M, Tahara T, Shibata T, Yamashita H, Nakamura M, Yoshioka D, et al. Association study of common genetic variants in pre-microRNAs in patients with ulcerative colitis. J Clin Immunol. 2010;31(1):69–73.PubMedCrossRefGoogle Scholar
  33. 33.
    He BS, Pan YQ, Cho WC, Xu YQ, Gu L, Nie ZL, Chen LP, Song GQ, Gao TY, Li R, Wang SK. The association between four genetic variants in microRNAs (rs11614913, rs2910164, rs3746444, rs2292832) and cancer risk: evidence from published studies. PLoS ONE 7(11): e49032.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Bing Zhou
    • 1
  • Liang-peng Dong
    • 1
  • Xiao-yue Jing
    • 1
  • Jin-song Li
    • 2
  • Shu-juan Yang
    • 3
  • Jun-ping Wang
    • 4
  • Long-feng Zhao
    • 5
  1. 1.Department of General SurgeryThe First Affiliated Hospital of Xinxiang Medical UniversityWeihuiChina
  2. 2.Department of Pathology DepartmentThe First Affiliated Hospital of Xinxiang Medical UniversityWeihuiChina
  3. 3.Department of Child, Adolescent and Maternal Health, West China School of Public HealthSichuan UniversityChengduChina
  4. 4.Shanxi Provincial People’s HospitalTaiyuanChina
  5. 5.The First of Hospital of Shanxi Medical UniversityTaiyuanChina

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