Genetic Variation in a MicroRNA-502 Minding Site in SET8 Gene Confers Clinical Outcome of Non-Small Cell Lung Cancer in a Chinese Population

Abstract

BackgroundGenetic 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.MethodsUsing 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.ResultsLog-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).ConclusionOur 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.

SET8 expression is associated with overall survival in gastric cancer

“…However, no studies have demonstrated a correlation between SET8 and gastric cancer. In this study, we analyzed the association between SET8 expression and gastric cancer risk and outcome, and found that the lower SET8 expression group had a higher survival rate, which is consistent with the data of a previous study Xu et al, 2013).…”

“…SET8 has been shown to be correlated with a series of human tumors, such as hepatocellular cancer, breast cancer, ovarian cancer, and lung cancer (Song et al, 2009;Ding et al, 2012;Guo et al, 2012;Wang et al, 2012;Xu et al, 2013). However, no studies have demonstrated a correlation between SET8 and gastric cancer.…”

“…Previous studies found that modulation of SET8 protein expression contributes to breast cancer and ovarian cancer susceptibility and affects the clinical outcome of hepatocellular carcinoma and non-small cell lung cancer (Song et al, 2009;Guo et al, 2012;Wang et al, 2012;Xu et al, 2013). Lower SET8 levels were found to be associated with longer survival in hepatic carcinoma and nonsmall cell lung cancer patients Xu et al, 2013). In this study, we assessed the predictive capacity of SET8 on gastric cancer prognosis.…”

“…In particular, targeting H4K20 for monomethylation (Fang et al, 2002;Nishioka et al, 2002) has been shown to have important functions in diverse biological processes, such as gene transcriptional control, replication origin modulation, genome integrity maintenance, cell cycle progression, and development (Abbas et al, 2010;Centore et al, 2010;Oda et al, 2010;Jørgensen et al, 2011;Li et al, 2011). Previous studies found that modulation of SET8 protein expression contributes to breast cancer and ovarian cancer susceptibility and affects the clinical outcome of hepatocellular carcinoma and non-small cell lung cancer (Song et al, 2009;Guo et al, 2012;Wang et al, 2012;Xu et al, 2013). Lower SET8 levels were found to be associated with longer survival in hepatic carcinoma and nonsmall cell lung cancer patients Xu et al, 2013).…”

A single nucleotide polymorphism in the promoter region of let-7 family is associated with lung cancer risk in Chinese

“…rs16917496 in SET8 3'-untranslated region (UTR), a binding site of miR-502, was related to cancer survival. The CC genotype was associated with longer survival time and a decreased risk of death in NSCLC patients (Xu et al, 2013a). Similarly, the CC+CT genotype was closely associated with longer survival of SCLC patients (Ding et al, 2012).…”