Polymorphisms involved in the miR-218-LAMB3 pathway and susceptibility of cervical cancer, a case–control study in Chinese women

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Abstract

Objective

Laminin-5 is required in RAS and NF-kappaB blockade induced tumorigenesis of human squamous cell carcinoma and a marker of invasiveness in cervical lesions. MicroRNA-218 (miR-218) can target laminin-5 β3 (LAMB3), but suppressed by HPV-16 E6 protein. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in pri-miR-218 and LAMB3 may individually and/or jointly contribute to cervical cancer carcinogenesis.

Methods

We identified one SNP rs11134527 located in pri-miR-218 sequence and one SNP rs2566 in 3′UTR of LAMB3 and genotyped these two SNPs in a case–control study of 703 cervical cancer cases and 713 cancer-free controls in Chinese women.

Results

Logistic regression analyses showed that the pri-miR-218 rs11134527 variant homozygote GG was associated with a decreased risk of cervical cancer compared with the AA genotype (adjusted OR = 0.72, 95% CI = 0.52–0.99), while the LAMB3 rs2566 variant CT/TT genotypes were associated with a significantly increased risk of cervical cancer (adjusted OR = 1.57, 95% CI = 1.25–1.96), compared with the wild type CC genotype. A significant dose–response effect was observed between the number of risk alleles, rs11134527A and rs2566 T, and the risk of cervical cancer (P for trend = 0.0006).

Conclusion

These findings indicate that pri-miR-218 rs11134527 and LAMB3 rs2566 may contribute to cervical cancer carcinogenesis, and further validations in diverse populations and functional characterizations are warranted.

Introduction

Cervical cancer is the second most common cancer among women worldwide, with an estimated 493,000 new cases and 274,000 deaths in the year 2002 [1]. It is well established that Human Papillomavirus (HPV) infection is the primary cause of cervical cancer and is indeed deemed as a necessary cause for the disease [1], [2], [3]. High-risk HPV E6 and E7 oncoproteins can inactivate critical tumor suppressors, which makes the virus override cell cycle checkpoints and cause cellular transformation [2], [4]. It is well characterized that the HPV oncoprotein E6 can degrade p53 through the ubiquitin pathway, and studies also showed that HPV E6/E7 oncoproteins can interact with certain proteins to modify the development of cervical cancer [2], [3], [4], [5], [6].

Except protein coding genes, a recent study showed that the expression of the E6 oncoprotein of the high-risk HPV-16 could reduce microRNA-218 (miR-218) expression [7]. Conversely, RNA interference of E6/E7 oncogenes in an HPV-16-positive cell-line could increase miR-218 expression [7]. MicroRNAs (miRNAs) are small noncoding RNAs that may regulate thousands of mRNA targets by binding to their 3′ untranslated regions (3′-UTR) [8], and these targets could be implicated in the regulation of almost all biological processes [9], [10]. Laminin-5 β3 (LAMB3) has been verified as a transcriptional target of miR-218 [7] and the expression of LAMB3 is increased in the presence of the HPV-16 E6 oncoprotein and this effect is mediated through miR-218 [7]. Interestingly, laminin-5 is reported as a marker of invasiveness in cervical lesions [11], and is required for RAS and NF-kappaB blockade induced tumorigenesis of human squamous cell carcinoma [12], [13]. A recent study also reported that secreted laminin-5 can be used by HPV virus as a transient receptor to aid the virus in the infection of basal cells that express a6b4-integrin [14]. Thus, downregulation of miR-218 by E6 and the consequent over expression of LAMB3 may promote viral infection of the surrounding tissue and eventually contribute to cervical carcinogenesis (Fig. 1).

Sequence variations in miRNA genes, including pri-miRNAs (primary miRNAs), pre-miRNAs (precursor miRNAs) and mature miRNAs, could influence the processing and/or target binding of miRNAs [15]. In our previous studies, we found that single nucleotide polymorphisms (SNPs) in pre-miRNAs may contribute to both cancer susceptibility and prognosis [16], [17], [18]. In the present study, we hypothesized that polymorphisms involved in the miR-218-LAMB3 pathway may alter the expression of miRNA-218 or LAMB3 and/or maturation of miRNA-218, and therefore individually and/or jointly contribute to cervical cancer risk. To test the hypothesis, we performed genotyping analysis for 2 SNPs in pri-miR-218 and LAMB3 in a case–control study of 703 cervical cancer cases and 713 age frequency-matched cancer-free controls in Chinese women.

Section snippets

Participants

The study was approved by the Institutional Review Board of Nanjing Medical University and the recruitment of the cases and controls was partly described previously [19]. Briefly, all of the cases and control subjects were unrelated ethnic Han Chinese women. The 703 newly diagnosed, histologically confirmed incident cervical cancer patients were consecutively recruited from the First Affiliated Hospital of Nanjing Medical University and the Nantong Tumor Hospital, Jiangsu, China between March

Results

Selected characteristics of the 703 cervical cancer cases and the 713 cancer-free controls were described in Table 1. As expected, there was similar distribution of age in cases and controls (P = 0.811). However, compared with the control subjects, the cervical cancer cases had significantly lower age at menarche (P = 0.003) and at first live birth (P < 0.0001), had higher proportion of smokers (P = 0.001), of premenopausal women (P = 0.015), and of women with higher parity (P = 0.005) and family history

Discussion

To the best of our knowledge, this is the first study to provide evidence that SNPs involved in the miR-218-LAMB3 pathway may play a role in cervical carcinogenesis and more importantly, these 2 SNPs may jointly be associated the susceptibility of cervical cancer in Chinese women. Further characterizations of the function of these SNPs, genes and the miR-218-LAMB3 pathway may improve our understanding of cervical cancer development.

Laminin-5 has long been suggested as a marker of invasiveness

Conflict of interest statement

None declared.

Acknowledgments

This work was supported in part by the Program for Changjiang Scholars and Innovative Research Team in University(IRT0631); Key Project of Nanjing Medical University(07NMUZ011), Natural Science Foundation of Jiangsu Colleges(08KJB330002) and Project for Public Technology Service Center for Reproductive Health in Humans (BM2007709 and BM2008151).

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