Genetic variants in microRNA target sites of 37 selected cancer-related genes and the risk of cervical cancer.
OBJECTIVE
Single 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.


METHODS
We 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.


RESULTS
Five 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).


CONCLUSIONS
These 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.
Obstetrical department, Maternal and Child Health Hospital of Shaanxi Province, Xi'an, ShaanXi, Peoples' Republic of China.
Yang
Y
Mi
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, ShaanXi, Peoples' Republic of China.
Lijuan
L
Wang
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, ShaanXi, Peoples' Republic of China.
Lu
L
Zong
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, ShaanXi, Peoples' Republic of China.
Meili
M
Pei
Department of Pathology, Liaocheng People's Hospital, Liaocheng, ShanDong, Peoples' Republic of China.
Qingyang
Q
Lu
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, ShaanXi, Peoples' Republic of China.
Pu
P
Huang
D020413:3' Untranslated Regions; D000328:Adult; D052685:Alphapapillomavirus / Q000235:genetics; D020029:Base Pairing; D001483:Base Sequence; D001665:Binding Sites; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D019410:Interleukin-16 / Q000097:blood / Q000737:chemistry / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D012306:Risk; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology
D020413:3' Untranslated Regions; D019410:Interleukin-16; D035683:MicroRNAs