Open AccessGenetic Variation in a MicroRNA-502 Minding Site in SET8 Gene Confers Clinical Outcome of Non-Small Cell Lung Cancer in a Chinese Population
Author(s) -
Jiali Xu,
Zhiqiang Yin,
Wen Gao,
Lingxiang Liu,
Yongmei Yin,
Ping Liu,
Yongqian Shu
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0077024
Subject(s) - genotype , lung cancer , biology , allele , hazard ratio , single nucleotide polymorphism , population , immunostaining , microbiology and biotechnology , cancer research , oncology , genetics , gene , medicine , confidence interval , immunology , immunohistochemistry , environmental health
Background Genetic variants may influence microRNA-target interaction through modulate their binding affinity, creating or destroying miRNA-binding sites. SET8, a member of the SET domain-containing methyltransferase, has been implicated in a variety array of biological processes. Methods Using Taqman assay, we genotyped a polymorphism rs16917496 T>C within the miR-502 binding site in the 3′-untranslated region of the SET8 gene in 576 non-small cell lung cancer (NSCLC) patients. Functions of rs16917496 were investigated using luciferase activity assay and validated by immunostaining. Results Log-rank test and cox regression indicated that the CC genotype was associated with a longer survival and a reduced risk of death for NSCLC [58.0 vs. 41.0 months, P = 0.031; hazard ratio = 0.44, 95% confidential interval: 0.26–0.74]. Further stepwise regression analysis suggested rs16917496 was an independently favorable factor for prognosis and the protective effect more prominent in never smokers, patients without diabetes and patients who received chemotherapy. A significant interaction was observed between rs16917496 and smoking status in relation to NSCLC survival ( P <0.001). Luciferase activity assay showed a lower expression level for C allele as compared with T allele, and the miR-502 had an effect on modulation of SET8 gene in vitro . The CC genotype was associated with reduced SET8 protein expression based on immunostaining of 192 NSCLC tissue sample ( P = 0.007). Lower levels of SET8 were associated with a non-significantly longer survival (55.0 vs. 43.1 months). Conclusion Our data suggested that the rs16917496 T>C located at miR-502 binding site contributes to NSCLC survival by altering SET8 expression through modulating miRNA-target interaction.