Association between indel polymorphism in the promoter region of lncRNA GAS5 and the risk of hepatocellular carcinoma

Abstract

The growth arrest special 5 (GAS5) is known to be involved in various cancers. However, its expression regulation remains unclear. Polymorphisms in the promoter region of GAS5 may affect its expression and be associated with cancer susceptibility. In this research, we first evaluated the association of a 5-base pair indel polymorphism (rs145204276) in the promoter region of GAS5 with hepatocelluar carcinoma (HCC) susceptibility in Chinese populations. Logistic regression analysis showed that the deletion allele of rs145204276 significantly increased the risk of HCC in two independent case control sets (1034 HCC and 1054 controls). Further genotype-phenotype association analysis revealed that the deletion allele was markedly correlated with higher expression of GAS5 in HCC tissues. The luciferase activity analysis in an in vitro reporter gene system suggested that the deletion allele improved an increased expression of GAS5 in three hepatoma cell lines. Intriguingly, overexpression of GAS5 displayed an anti-apoptosis effect in HCC cell lines, GAS5 knockdown could partially revert this anti-apoptosis effect, suggesting that GAS5 may act as a proto-oncogene in HCC, in contrast with its inhibitory role in other cancers. Further pyrosequencing revealed that the genotypes of rs145204276 were associated with methylation status of GAS5 promoter region. Taken together, our findings provided evidence that rs145204276 may contribute to hepatocarcinogenesis by affecting methylation status of the GAS5 promoter and subsequently its transcriptional activity thus serving as a potential therapy target for HCC.

Association Between the Deletion Allele of Ins/Del Polymorphism (Rs145204276) in the Promoter Region of GAS5 with the Risk of Atherosclerosis

“…Growing data have revealed that SNPs in some lncRNAs are associated with chemotherapy response and tumorigenesis [22]. For example, the rs145204276 located in the promoter region of GAS5 has been reported to be an endogenous competing RNA of miR-21 [23][24][25]. Also, PDCD4 is believed to play a critical function in the pathogenesis of atherosclerosis by modulating the apoptosis of vascular endothelial cells [26,27], while our in-silicon analysis also found that miR-21 virtually targeted PDCD4.…”

“…Interestingly, an earlier study has suggested that non-coding RNAs Zfas1 and GAS5 acted as tumor inhibitors, while the down-regulation of lncRNA GAS5 was found in prostate cancer, non-small cell lung cancer, breast cancer and renal cell carcinoma [30][31][32][33].Furthermore, an association between the rs145204276 polymorphism in the promoter region of GAS5 and the risk of HCC has also been identified. Moreover, rs145204276 may be functionally involved in oncogenesis via modulating the methylation status of a CpG island situated in the GAS5 promoter region, thus influencing the activity and expression of GAS5 [25]. In this study, we conducted luciferase reporter assays using vectors carrying rs145204276 polymorphism INS and DEL alleles to determine the effect of rs145204276 on the transcriptional activity of GAS5.…”

Rs145204276 polymorphism of GAS5 is associated with renal fibrosis via miR-21/SMAD/TGF-β1 signaling pathway

“…The rs145204276 polymorphism of promoter region of GAS5 was related to susceptibility to HCC. The SNP alters a CpG island methylation status in the GAS5 promoter region, and then the transcriptional activity of GAS5 and finally the expression level of GAS5 [15].The promoter region of GAS5 the deletion allele of a 5-base pair indel polymorphism (rs145204276) greatly enhanced the expression of GAS5 in hepatocellular cell lines and increased the risk of hepatocellular carcinoma (HCC), and it indicated that the GAS5 played differential roles in carcinogenesis of different cancer types [15]. To examine if the rs145204276 polymorphism influences the expression of GAS5, we conducted luciferase assay and found that that the deletion allele significantly increased luciferase activity of GAS5.…”

“…The negative relationship between miR-21 and GAS5 has been detected in clinical breast cancer specimens [14]. One variant (rs145204276 polymorphism), located in the promoter region of GAS5, could alter the transcription ability of the promoter [15]. GAS5 functions as a sponge of miR-21, which inhibits SMAD7 expression, and SMAD7 competitively inhibits another family member of SMAD3 [16,17].…”

Roles of long noncoding RNAs in Hepatocellular Carcinoma

“…Indeed, lncRNAs affect cell proliferation, migration, apoptosis, invasion, tumorigenicity, cell cycle, and metastasis. [11][12][13] Furthermore, evidence is accumulating to suggest that the aberrant expressions of lncRNAs have a clinical impact on the diagnosis of hepatocellular carcinoma. In this regard lncRNAs are associated with clinicopathological features including metastasis, invasion, TNM stage, prognosis, tumor size, and differentiation of patients with hepatocellular carcinoma.…”