Elsevier

Human Immunology

Volume 71, Issue 6, June 2010, Pages 621-626
Human Immunology

Association of a variant in MIR 196A2 with susceptibility to hepatocellular carcinoma in male Chinese patients with chronic hepatitis B virus infection

https://doi.org/10.1016/j.humimm.2010.02.017Get rights and content

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions as tumor suppressors and oncogenes. Recent studies have implicated that the rs11614913 SNP in MIR196A2 was associated with susceptibility of lung cancer, congenital heart disease, breast cancer and shortened survival time of nonsmall cell lung cancer. To assess whether this polymorphism is associated with susceptibility to and clinicopathologic characteristics of hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC), a total of 560 patients with chronic HBV infection and 391 healthy volunteers were enrolled, and MIR196A2 polymorphism was genotyped by polymerase chain reaction–ligation detection reaction (PCR–LDR). In our study group, there was no significant association between MIR196A2 polymorphism and the risk of HBV-related HCC in all subjects, however, the risk of HCC was significantly higher with MIR196A2 rs11614913 CC genotype or C allele compared with those with the TT genotype or T allele in male patients. Furthermore, in a subsequent analysis of the association between this polymorphism and clinicopathologic characteristics, there was still no significant difference in both the distribution of genotype or allelic frequency. However, we observed that the T allele was significantly more frequent in male HCC patients with lymphatic metastasis. Our results suggested that MIR196A2 polymorphism was associated with susceptibility to HBV-related HCC in a male Chinese population.

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide [1]. The causes of more than 85% of HCC cases are known (hepatitis viruses B and C, aflatoxin B1, ethanol), but new risk factors continue to emerge (type II diabetes and obesity) [2], [3]. In China, HCC ranks second among all malignancies [4] and hepatitis-B virus (HBV) infection is highly endemic. However, the molecular mechanism of virus-induced carcinogenesis is still poorly understood. Therefore, a better understanding of the genes involved in tumor growth and progression is necessary for the development of novel diagnostic and therapeutic strategies that can improve the treatment of this deadly disease.

MicroRNAs (miRNAs) are a class of small, noncoding RNA molecules ∼20 nucleotides in length. miRNAs are initially transcribed as long primary transcripts (pri-miRNAs), which are then processed into ∼65-nucleotide hairpin-shaped precursor miRNAs (pre-miRNAs). Pre-miRNAs are further cleaved to produce mature miRNAs [5]. miRNAs play important roles in the etiology of many human diseases through post-transcriptionally regulating the expression of approximately one-third of all human genes [6]. A strong link between miRNAs and cancer has been demonstrated recently, opening up a new avenue of investigation for cancer biology [7]. At the present time, the main mechanism that underlies changes in the function of miRNAs in cancer cells seems to be aberrant gene expression, characterized by abnormal levels of expression for mature and/or precursor miRNA sequences compared with the corresponding normal tissues. miRNA expression profiles have been frequently reported to be correlated with the etiology, classification, progression, and prognosis of multiple human cancers, including HCC [8], [9], [10], [11], [12], [13], [14], [15], [16], [17].

The precise mechanisms regulating miRNA expression and maturation are largely unknown; studies have suggested several mechanisms, including genetic and epigenetic alterations [18], [19]. A mutation or a single nucleotide polymorphism (SNP) at the miRNA gene region might affect the transcription of pri-miRNA transcripts, the processing of miRNA precursors to mature miRNAs, or miRNA–target interactions [20]. Although SNPs in miRNA regions have been reported to be rare and unlikely to be functionally important [21], recent studies have implicated that genetic alterations of the miRNA biogenesis pathway may be associated with cancer development and progression [22]. Indeed, the rs11614913 SNP in MIR196A2 has been reported to be associated with susceptibility of lung cancer [23], congenital heart disease [24], breast cancer [25] and shortened survival time of non–small-cell lung cancer (NSCLC) [26] through altering the expression of mature miR-196a and binding activity of target mRNA. In light of the important role of miRNAs in HCC development and progression, we hypothesized that the functional SNP, rs11614913, in MIR196A2, was also associated with the susceptibility and/or progression of HBV-related HCC. To test this hypothesis, we genotyped MIR196A2 T>C polymorphism among 361 HCC patients with chronic HBV infection, 199 HBV patients without HCC, and 391 healthy volunteers with no evidence of recent or remote HBV infection. To our knowledge, this is the first study that evaluates the effects of MIR196A2 polymorphism on the risk and progression of HBV-related HCC.

Section snippets

Subjects

A total of 951 subjects were periodically enrolled between December 2006 and February 2008 at the Eastern Hepatobiliary Hospital, including 560 patients with chronic HBV infection and 391 healthy volunteers with no evidence of recent or remote HBV infection. The patients were divided into two groups: those without HCC (n = 199) and those with HCC (n = 361). These 361 HCC patients with chronic HBV infection were designated as cases, the remaining 199 patients without HCC and 391 healthy

General characteristics of the subjects

A total of 951 local ethnic Han Chinese subjects were enrolled in our study. General characteristics of the subjects are summarized in Table 1. The healthy controls were slightly younger than the two groups with disease, and the HBV-related HCC group had a higher proportion of male subjects. In addition, the HCC group and the other two groups without HCC (healthy controls and non-HCC patients with HBV infection) had statistically different laboratory results for ALB, T-Bil and ALT (p < 0.001).

Discussion

Early detection of high risk individuals in the population is one of the best strategies for preventing cancer. Molecular epidemiologic studies have shown that there was a significant association between the genetic polymorphism of some important genes, including Cytochrome P450 2E1 (CYP2E1) [29], CYP1A1 [30], UDP-glucuronosyltransferases (UGT) [31], N-acetyltransferase 2 (NAT 2) [32], glutathione-S-transferase M1 (GSTM1) [33], p53 [34], transforming growth factor–β1 (TGF-β1) [35], [36], and

Acknowledgments

This research was supported by National Natural Science Foundation of China Grant No. 30770994 and The State Key Project on Infection Disease of China No. 2008ZX10002-025. The authors declare that they have no competing financial interests.

References (46)

  • P. Qi et al.

    Virus-encoded microRNAs: Future therapeutic targets?

    Cell Mol Immunol

    (2006)
  • A. Esquela-Kerscher et al.

    Oncomirs-microRNAs with a role in cancer

    Nat Rev Cancer

    (2006)
  • Y. Murakami et al.

    Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues

    Oncogene

    (2006)
  • H. Kutay et al.

    Downregulation of miR122 in the rodent and human hepatocellular carcinomas

    J Cell Biochem

    (2006)
  • L. Gramantieri et al.

    Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma

    Cancer Res

    (2007)
  • H. Varnholt et al.

    MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma

    J Hepatol

    (2008)
  • Y.S. Huang et al.

    Microarray analysis of microRNA expression in hepatocellular carcinoma and non-tumorous tissues without viral hepatitis

    J Gastroenterol Hepatol

    (2008)
  • Y. Ladeiro et al.

    MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations

    J Hepatol

    (2008)
  • A. Budhu et al.

    Identification of metastasis-related microRNAs in hepatocellular carcinoma

    J Hepatol

    (2008)
  • J. Jiang et al.

    Association of microRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival

    Clin Cancer Res

    (2008)
  • A. Lujambio et al.

    Genetic unmasking of an epigenetically silenced microRNA in human cancer cells

    Cancer Res

    (2007)
  • R. Duan et al.

    Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA

    Hum Mol Genet

    (2007)
  • W. Yang et al.

    Modulation of microRNA processing and expression through RNA editing by ADARAdar deaminases

    Nat Struct Mol Biol

    (2006)
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