Polymorphism of the pre-miR-146a is associated with risk of cervical cancer in a Chinese population

https://doi.org/10.1016/j.ygyno.2011.03.032Get rights and content

Abstract

Objective

MicroRNAs are tiny non-coding RNAs that reportedly play an important role in numerous physiological processes. A G > C polymorphism (rs2910164) is located on the passenger strand of the precursor of miR-146a, which could alter mature miR-146a expression. We hypothesized that a possible association exists between miR-146a gene polymorphisms and cervical cancer risk in a population-based control study of female residents in Jiangsu Province.

Methods

The subjects included 447 cervical cancer cases and 443 cancer-free controls with frequency matched by age. We genotyped the functional polymorphism of miR-146a (rs2910164) by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method, and used a sample of 24 cervical cancer tissue to test the expression of miR-146a by real-time quantitative reverse transcription.

Results

Our study indicated that the subjects carrying GG homozygote had a 1.496-fold increased risk than those carrying CG/CC genotypes (95% CI = 1.068–2.095). Moreover, miR-146a quantification showed that the carriers of GG genotype had obviously more reduced miR-146a expression level compared with the carriers of CC genotype.

Conclusion

Our study suggests that the risk of cervical cancer in a Chinese population partly results from miRNA-146a expression deviation in vivo, being caused by common polymorphism in miR-146a. This is an initial study to indicate that miR-146a (rs2910164) might contribute to cervical cancer susceptibility.

Research Highlights

► We found that individuals with miR-146a rs2910164 GG genotype had increased risk of cervical cancer risk. ► Furthermore, the G to C change in miR-146a might cause elevated expression of mature miR-146a. ► Our findings suggest that miR-146a rs2910164 may be as a biomarker for developing cervical cancer.

Introduction

Cervical cancer is the most common malignancy in women worldwide, with an estimated global incidence of 493,243 new cases and tremendously high death cases of 273,505 per year [1]. The incidence and mortality have dropped significantly in developed countries due to effective cervical screening programs, but still remain high in developing countries, where 83% of annual new cases occur [2]. China, as the largest developing country in the world, has 135,000 new cases of cervical cancer each year, making up 1/3 of the global incidence [3]. A great proportion of young females who are active in sex with relatively more sexual partners can get infected with human papillomavirus (HPV), mainly consisting of types 16 and 18 [4]. Moreover, through a relatively weak immunity system some infectors' persistent infection might ultimately lead to cervical cancer. HPV infection is necessary but not sufficient for cervical cancer development [5]. Epidemiological studies have suggested that host genetic variations may also contribute to cervical cancer pathogenesis [6].

Recently discovered microRNAs (miRNAs) are class of small, endogenous, non-coding RNA molecules, which are about 17–22 nucleotides in length, and regulate gene expression by translational repression or mRNA degradation [7]. MiRNAs take effects by attaching to the 3′-untranslated region of their target messenger RNAs and target up to 30% of human genes [8]. It has been discovered that miRNAs have critical functions in various physiological processes ranging from cell proliferation and apoptosis to carcinogenesis [7], [9], [10], [11]. Small genetic changes in microRNA may alter the expression and/or target selection of human miRNAs [12]. The relationship between genetic variations in microRNA genes and cancer susceptibility has been getting more and more attention from academics and researchers, which has brought this subject to a deeper level.

The miRNA-146a polymorphism (rs2910164) involves a G > C nucleotide substitution which causes change from a G:U pair to a C:U mismatch in the stem structure of miR-146a precursor. This polymorphism can lead to process variation, lower expression of mature sequence and eventually predisposition of papillary thyroid carcinoma [13]. In this study, we hypothesized that the miR-146a polymorphism is associated with cervical cancer susceptibility. To test this hypothesis, we genotyped this particular single nucleotide polymorphism (SNP) (rs2910164) by using a hospital-based case–control study of the population in Jiangsu Province. To further study the potential functional effect of polymorphism, we investigated the association of mature miR-146a expression level with cervical cancer susceptibility.

Section snippets

Study population

The study was approved by the institutional review board of Nanjing Medical University. This case–control study included 447 cervical cancer patients and 443 cancer-free test persons who were recruited during the period of March 2006 to January 2010 in the First Affiliated Hospital of Nanjing Medical University and the Tumor Hospital of Nantong City, Jiangsu, China. All subjects were genetically-unrelated Han Chinese, and approximately 95% of them chose to participate after informed consents.

Characteristics of the study population

Basic characteristics of the study objects are presented in Table 1. Out of the 447 cervical cancer cases, 430 (96.20%) were squamous cell carcinoma, 14 (3.13%) were adenocarcinoma, 2 (0.45%) were adenosquamous carcinoma, and 1 (0.22%) was unknown. There were no statistically significant differences between cases and controls in terms of age, menopause status and number of abortions (P = 0.238, P = 0.241 and P = 0.270, respectively). However, compared with control subjects, the cervical cancer cases

Discussion

In this study, we focused on the influence of miR-146a gene polymorphisms on individual's genetic susceptibility to cervical cancer and the expression of miR-146a with different genotypes in cervical cancer tissue. We found that individuals carrying GG genotype of miR-146a gene had increased risk than those carrying CG/CC genotypes. In addition, this G to C change in the precursor of miR-146a tends to cause elevated expression of mature miR-146a.

Studies of association between cancer

Conclusion

Our results provided the first insight into the functional polymorphism of mir-146a contribution to cervical cancer susceptibility by affecting the amount of mature miR-146a. The functional role of mir-146a polymorphism, including expression of miR-146a in transfected cervical cancer cells and impact of SNP on miR-146a target genes remains to be explored. Furthermore, clinical relevance of pre-miR-146a polymorphism to chemotherapy response or environmental exposure, HPV infection and relating

Conflict of interest statement

The authors declare no conflict of interest.

Acknowledgment

This study was partly supported by the Natural Science Foundation of Jiangsu Province (BK2009418).

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      Furthermore, in another meta-analysis, Xu and colleagues have reported the protection role of miR-146a C allele in the digestive cancers (Xu et al., 2011). In accordance with our result, Yue et al. have indicated that miR-146a GG variant versus GC/CC variants increases to 1.496-fold the risk of cervical neoplasm occurrence in Chinese population (Yue et al., 2011) and it is agree with the findings presented by Guo et al. in a case-control research of 444 patients with esophageal squamous cell carcinoma and 468 healthy people in Chinese population. In this study, it is shown that risk of the cancer for people carrying GG genotype is 2.39 times greater compared people with CC genotype (Guo et al., 2010).

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