Skip to main content
SpringerLink
Log in

Genetic variants in miR-196a2 and miR-499 are associated with susceptibility to esophageal squamous cell carcinoma in Chinese Han population

  • Original Article
  • Published:
Tumor Biology

Abstract

Esophageal squamous cell carcinoma (ESCC) is the dominant type of esophageal cancer in the East Asian population. MicroRNAs (miRNAs) have been studied to play important roles in tumorigenesis. Single nucleotide polymorphisms (SNPs) in miRNA lead to the aberrant expression and structural alteration of miRNA and are hypothesized to be involved in tumorigenesis and cancer development. We conducted a population-based case-control study to evaluate the association between SNPs in miRNAs and ESCC risk in 1400 ESCC cases and 2185 matched controls. Four SNPs including miR-196a2 rs11614913, miR-146a rs2910164, miR-499 rs3746444, and miR-423 rs6505162 were selected with comprehensive collection strategy and genotyped using the SNaPshot Multiplex System. Odds ratio (OR) and 95 % confidence interval (95 % CI) were used to assess the strength of association. The CC genotype of miR-196a2 rs11614913 was significantly associated with an increased ESCC risk compared with the TT genotype (OR 1.11, 95 % CI 1.01–1.22, P 0.049) and the TT/TC genotypes (OR 1.09, 95 % CI 1.01–1.19, P 0.043). The association was more pronounced in non-drinkers in the recessive model (OR 1.13, 95 % CI 1.01–1.27, P 0.029). A significantly increased risk of ESCC associated with miR-499 rs3746444 polymorphism was evident among patients who never smoking and drinking. This study suggests that miR-196a2 rs11614913 and miR-499 rs3746444 are associated with an increased ESCC risk in a Chinese population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

CI:

Confidence interval

ESCC:

Esophageal squamous cell carcinoma

miRNA:

MicroRNA

OR:

Odds ratio

SNP:

Single nucleotide polymorphism

ROC:

Receiver operating characteristic

AUC:

Area under the curve

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.

    Article  PubMed  Google Scholar 

  2. Vizcaino AP, Moreno V, Lambert R, Parkin DM. Time trends incidence of both major histologic types of esophageal carcinomas in selected countries, 1973–1995. Int J Cancer. 2002;99(6):860–8.

    Article  CAS  PubMed  Google Scholar 

  3. Levine DM, Ek WE, Zhang R, Liu X, Onstad L, Sather C, et al. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett’s esophagus. Nat Genet. 2013;45(12):1487–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bass AJ, Meyerson M. Genome-wide association study in esophageal squamous cell carcinoma. Gastroenterology. 2009;137(5):1573–6.

    Article  CAS  PubMed  Google Scholar 

  5. Guo S, Wang YL, Li Y, Jin L, Xiong M, Ji QH, et al. Significant SNPs have limited prediction ability for thyroid cancer. Cancer Med. 2014;3(3):731–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang P, Wang J, Lu T, Wang X, Zheng Y, Guo S, et al. miR-449b rs10061133 and miR-4293 rs12220909 polymorphisms are associated with decreased esophageal squamous cell carcinoma in a Chinese population. Tumour Biol. Jun 9 2015.

  7. Guo H, Wang K, Xiong G, Hu H, Wang D, Xu X, et al. A functional varient in microRNA-146a is associated with risk of esophageal squamous cell carcinoma in Chinese Han. Fam Cancer. 2010;9(4):599–603.

    Article  PubMed  Google Scholar 

  8. Gen Y, Yasui K, Zen Y, Zen K, Dohi O, Endo M, et al. Sox2 identified as a target gene for the amplification at 3q26 that is frequently detected in esophageal squamous cell carcinoma. Cancer Genet Cytogenet. 2010;202(2):82–93.

    Article  CAS  PubMed  Google Scholar 

  9. Hu N, Clifford RJ, Yang HH, Wang C, Goldstein AM, Ding T, et al. Genome wide analysis of DNA copy number neutral loss of heterozygosity (CNNLOH) and its relation to gene expression in esophageal squamous cell carcinoma. BMC Genomics. 2010;11:576.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Zempleni J, Baier SR, Howard KM, Cui J. Gene regulation by dietary microRNAs. Can J Physiol Pharmacol. 2015;14:1–6.

    Google Scholar 

  11. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.

    Article  CAS  PubMed  Google Scholar 

  12. Li Y, Kowdley KV. MicroRNAs in common human diseases. Genomics Proteomics Bioinformatics. 2012;10(5):246–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Krutzfeldt J, Stoffel M. MicroRNAs: a new class of regulatory genes affecting metabolism. Cell Metab. 2006;4(1):9–12.

    Article  CAS  PubMed  Google Scholar 

  14. Nicoloso MS, Sun H, Spizzo R, Kim H, Wickramasinghe P, Shimizu M, et al. Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility. Cancer Res. 2010;70(7):2789–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Setoyama T, Ling H, Natsugoe S, Calin GA. Non-coding RNAs for medical practice in oncology. Keio J Med. 2011;60(4):106–13.

    Article  CAS  PubMed  Google Scholar 

  16. Tong N, Xu B, Shi D, Du M, Li X, Sheng X, et al. Hsa-miR-196a2 polymorphism increases the risk of acute lymphoblastic leukemia in Chinese children. Mutat Res. 2013;28:16–21.

    Google Scholar 

  17. Hoffman AE, Zheng T, Yi C, Leaderer D, Weidhaas J, Slack F, et al. microRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis. Cancer Res. 2009;69(14):5970–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Okubo M, Tahara T, Shibata T, Yamashita H, Nakamura M, Yoshioka D, et al. Association between common genetic variants in pre-microRNAs and gastric cancer risk in Japanese population. Helicobacter. 2010;15(6):524–31.

    Article  CAS  PubMed  Google Scholar 

  19. Ahn DH, Rah H, Choi YK, Jeon YJ, Min KT, Kwack K, et al. Association of the miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G polymorphisms with gastric cancer risk and survival in the Korean population. Mol Carcinog. 2013;52 Suppl 1:E39–51.

    Article  CAS  PubMed  Google Scholar 

  20. Wang X, Lu M, Qian J, Yang Y, Li S, Lu D, et al. Rationales, design and recruitment of the Taizhou Longitudinal Study. BMC Public Health. 2009;9:223.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yuan Z, Zeng X, Yang D, Wang W, Liu Z. Effects of common polymorphism rs11614913 in Hsa-miR-196a2 on lung cancer risk. PLoS ONE. 2013;8(4):e61047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang PY, Gao ZH, Jiang ZH, Li XX, Jiang BF, Xie SY. The associations of single nucleotide polymorphisms in miR-146a, miR-196a and miR-499 with breast cancer susceptibility. PLoS ONE. 2013;8(9):e70656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Peng S, Kuang Z, Sheng C, Zhang Y, Xu H, Cheng Q. Association of microRNA-196a-2 gene polymorphism with gastric cancer risk in a Chinese population. Dig Dis Sci. 2010;55(8):2288–93.

    Article  CAS  PubMed  Google Scholar 

  24. Akkiz H, Bayram S, Bekar A, Akgollu 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.

    Article  CAS  PubMed  Google Scholar 

  25. Wang K, Guo H, Hu H, Xiong G, Guan X, Li J, et al. A functional variation in pre-microRNA-196a is associated with susceptibility of esophageal squamous cell carcinoma risk in Chinese Han. Biomarkers. 2010;15(7):614–8.

    Article  CAS  PubMed  Google Scholar 

  26. Wei J, Zheng L, Liu S, Yin J, Wang L, Wang X, et al. MiR-196a2 rs11614913 T > C polymorphism and risk of esophageal cancer in a Chinese population. Hum Immunol. 2013;74(9):1199–205.

    Article  CAS  PubMed  Google Scholar 

  27. Xiang Y, Fan S, Cao J, Huang S, Zhang LP. Association of the microRNA-499 variants with susceptibility to hepatocellular carcinoma in a Chinese population. Mol Biol Rep. 2012;39(6):7019–23.

    Article  CAS  PubMed  Google Scholar 

  28. Zhou B, Wang K, Wang Y, Xi M, Zhang Z, Song Y, et al. Common genetic polymorphisms in pre-microRNAs and risk of cervical squamous cell carcinoma. Mol Carcinog. 2011;50(7):499–505.

    Article  CAS  PubMed  Google Scholar 

  29. Ye Y, Wang KK, Gu J, Yang H, Lin J, Ajani JA, et al. Genetic variations in microRNA-related genes are novel susceptibility loci for esophageal cancer risk. Cancer Prev Res (Phila). 2008;1(6):460–9.

    Article  CAS  Google Scholar 

  30. Umar M, Upadhyay R, Prakash G, Kumar S, Ghoshal UC, Mittal B. Evaluation of common genetic variants in pre-microRNA in susceptibility and prognosis of esophageal cancer. Mol Carcinog. 2013;52 Suppl 1:E10–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the grant from the National Natural Science Foundation of China (grant number 81071957), National Natural Science Foundation of China (grant number 81572923), a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Key Project in the National Science & Technology Pillar Program (grant number 2011BAI09B00), The Ministry of Health (grant number 201002007), and the funds from “China’s Thousand Talents Program” at Fudan University.

Author information

Author notes

    Authors and Affiliations

    1. Department of Biochemistry and Molecular Biology, Medical College, Soochow University, Ren’ai Road 199, 215123, Suzhou, China

      Fangyuan Shen, Yinghui Zhou, Yabiao Zheng, Junjie Zhang, Chenji Wang, Dunmei Zhao, Lixia Fan & Minghua Wang

    2. China National Center for Biotechnology Development, Beijing, China

      Jiejun Chen

    3. MOE Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Handan Road 220, 200433, Shanghai, China

      Shicheng Guo, Yajun Yang, Xiaofeng Wang, Li Jin & Jiucun Wang

    4. Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China

      Mengyun Wang, Meiling Zhu & Qingyi Wei

    5. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

      Mengyun Wang, Meiling Zhu & Jiaqing Xiang

    6. Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

      Jiaqing Xiang

    7. College of Acupuncture-Moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China

      Yong Xia

    8. Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA

      Qingyi Wei

    Authors
    1. Fangyuan Shen
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jiejun Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Shicheng Guo
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yinghui Zhou
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yabiao Zheng
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Yajun Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Junjie Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Xiaofeng Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Chenji Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Dunmei Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Mengyun Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Meiling Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Lixia Fan
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Jiaqing Xiang
      View author publications

      You can also search for this author in PubMed Google Scholar

    15. Yong Xia
      View author publications

      You can also search for this author in PubMed Google Scholar

    16. Qingyi Wei
      View author publications

      You can also search for this author in PubMed Google Scholar

    17. Li Jin
      View author publications

      You can also search for this author in PubMed Google Scholar

    18. Jiucun Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    19. Minghua Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Jiucun Wang or Minghua Wang.

    Ethics declarations

    Conflicts of interest

    None

    Additional information

    Conflicts of interest

    None

    Authors’ contribution

    LJ, JW, and MW designed the experiments. SG, JC, and MW selected SNP sites. FS, CW, DZ, MZ, and LF extracted genomic DNA from the samples and genotyping. SG, YZ, JZ, and JW performed the statistical analysis. FS, YZ, and JZ drafted the manuscript. JC, YY, XW, MW, MZ, and YX revised the manuscript. JW, QW, LJ, and JX collected and provided material samples and gave final approval of the version to be published. All authors read and approved the final manuscript.

    Fangyuan Shen, Jiejun Chen and Shicheng Guo contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Shen, F., Chen, J., Guo, S. et al. Genetic variants in miR-196a2 and miR-499 are associated with susceptibility to esophageal squamous cell carcinoma in Chinese Han population. Tumor Biol. 37, 4777–4784 (2016). https://doi.org/10.1007/s13277-015-4268-3

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s13277-015-4268-3

    Keywords

    Search

    Navigation