Abstract
ObjectivesSingle nucleotide polymorphisms (SNPs) in putative microRNA binding sites (miRSNPs) modulate cancer susceptibility via affecting miRNA binding. Here, we sought to investigate the association between miRSNPs and cervical cancer risk.MethodsWe first genotyped 41 miRSNPs of 37 cancer-related genes in 338 patients and 334 controls (Study 1), and replicated the significant associations in 502 patients and 600 controls (Study 2). We tested the effects of miRSNPs on microRNA-mRNA interaction by luciferase reporter assay.ResultsFive SNPs displayed notable association with cervical cancer risk in Study 1. Only IL-16 rs1131445 maintained a significant association with cervical cancer (CT/CC vs. TT, adjusted OR = 1.51, P = 0.001) in Study 2. This association was more evident in the combined data of two studies (adjusted OR = 1.49, P = 0.00007). We also found that miR-135b mimics interacted with IL-16 3′-UTR to reduce gene expression and that the rs1131445 T to C substitution within the putative binding site impaired the interaction of miR-135b with IL-16 3′-UTR. An ELISA indicated that the serum IL-16 of patients with cervical cancer was elevated (vs. controls, P = 0.001) and correlated with the rs1131445 genotype. Patients who carried the rs1131445 C allele had higher serum IL-16 than non-carriers (P<0.001).ConclusionsThese results support our hypothesis that miRSNPs constitute a susceptibility factor for cervical cancers. rs1131445 affects IL-16 expression by interfering with the suppressive function of miR135b and this variant is significantly associated with cervical cancer risk.
Highlights
Cervical cancer, the third most common cancer in women [1], is mainly caused by human papillomavirus (HPV) infection [2]
HPV infections are prevalent in sexually active women, only a minority of infections persist and develop into cervical intraepithelial neoplasia grade 2/3 (CIN 2/3) or even cervical cancer [3]
The cases were more likely to be younger at age at first delivery (P = 0.038) and with HPV infection (P,0.001) than the controls
Summary
The third most common cancer in women [1], is mainly caused by human papillomavirus (HPV) infection [2]. HPV infections are prevalent in sexually active women, only a minority of infections persist and develop into cervical intraepithelial neoplasia grade 2/3 (CIN 2/3) or even cervical cancer [3]. Several cofactors affect the transition from initial HPV infection to cervical cancer, including life-style, host immune response, and genetic susceptibility [4,5]. A few risk-modulating variants for cervical cancer have been identified by a candidate gene association study. The genes that are associated with cervical cancer susceptibility are involved in DNA repair, cellular cycle and apoptosis, cell proliferation and differentiation, the human leukocyte antigen system and immune responses [7,8]
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