AIMTo evaluate the association of 12 tag single nucleotide polymorphisms (tagSNPs) in three onco-long non-coding RNA (lncRNA) genes (HOTTIP, CCAT2, MALAT1) with the risk and prognosis of hepatocellular cancer (HCC).METHODSTwelve tagSNPs covering the three onco-lncRNAs were genotyped by the KASP method in a total of 1338 samples, including 521 HCC patients and frequency-matched 817 controls. The samples were obtained from an unrelated Chinese population at the First Hospital of China Medical University from 2012-2015. The expression quantitative trait loci (eQTL) analyses were conducted to explore further the potential function of the promising SNPs.RESULTSThree SNPs in HOTTIP, one promoter SNP in MALAT1, and one haplotype of HOTTIP were associated with HCC risk. The HOTTIP rs17501292, rs2067087, and rs17427960 SNPs were increased to 1.55-, 1.20-, and 1.18-fold HCC risk under allelic models (P = 0.012, 0.017 and 0.049, respectively). MALAT1 rs4102217 SNP was increased to a 1.32-fold HCC risk under dominant models (P = 0.028). In addition, the two-way interaction of HOTTIP rs17501292-MALAT1 rs619586 polymorphisms showed a decreased effect on HCC risk (Pinteraction = 0.028, OR = 0.30) and epistasis with each other. HOTTIP rs3807598 variant genotype showed significantly longer survival time in HBV negative subgroup (P = 0.049, HR = 0.12), and MALAT1 rs591291 showed significantly better prognosis in female and HBV negative subgroups (P = 0.022, HR = 0.37; P = 0.042, HR = 0.25, respectively). In the study, no significant effect was observed in eQTL analysis.CONCLUSIONSpecific lncRNA (HOTTIP and MALAT1) SNPs have potential to be biomarkers for HCC risk and prognosis.
MicroRNAs could mediate the targeted coding gene and the targeted non-coding RNA to form endogenous competition, which have an important regulatory role in tumorigenesis of many types of cancer, including hepatocellular carcinoma. The goal of this study was to characterize the role of miR-200b in the pathogenesis of hepatocellular carcinoma. We identified miR-200b that was predicted to regulate RhoA and circ_000839. Our data establish that miR-200b is expressed at a relatively low level in hepatocellular carcinoma ( p < 0.001). RhoA and circ_000839 are expressed at a relatively high level in hepatocellular carcinoma ( p < 0.001, respectively). Our mechanistic data indicate that RhoA is a direct target of miR-200b ( p < 0.001), binding of which affects the expression of invasion and migration in hepatocellular carcinoma cell lines ( p < 0.05). And correlation analysis showed that miR-200b was inversely correlated with RhoA and circ_000839 ( p = 0.012, p = 0.002, respectively), while RhoA was positively correlated with circ_000839 ( p < 0.001). Taken together, our data suggest that miR-200b could mediate RhoA gene and circ_000839 to form endogenous competition. And this is a direction for the association study of miR-200b and RhoA in the future.
Transfer RNA-derived small RNA(tsRNA) is a type of non-coding tRNA undergoing cleavage by specific nucleases such as Dicer. TsRNAs comprise of tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs). Based on the splicing site within the tRNA, tRFs can be classified into tRF-1, tRF-2, tRF-3, tRF-5, and i-tRF. TiRNAs can be classified into 5′-tiRNA and 3′-tiRNA. Both tRFs and tiRNAs have important roles in carcinogenesis, especially cancer of digestive system. TRFs and tiRNAs can promote cell proliferation and cell cycle progression by regulating the expression of oncogenes, combining with RNA binding proteins such as Y-box binding protein 1 (YBX1) to prevent transcription. Despite many reviews on the basic biological function of tRFs and tiRNAs, few have described their correlation with tumors especially gastrointestinal tumor. This review focused on the relationship of tRFs and tiRNAs with the biological behavior, clinicopathological characteristics, diagnosis, treatment and prognosis of digestive system tumors, and would provide novel insights for the early detection and treatment of digestive system tumors.
The current prognostic long noncoding RNA (lncRNA) signatures for hepatocellular carcinoma (HCC) are still controversial and need to be optimized by systematic bioinformatics analyses with suitable methods and appropriate patients. Therefore, we performed the study to establish a credible lncRNA signature for HCC outcome prediction and explore the related mechanisms. Based on the lncRNA profile and the clinical data of carefully selected HCC patients (n = 164) in TCGA, six of 12727 lncRNAs, MIR22HG, CTC‐297N7.9, CTD‐2139B15.2, RP11‐589N15.2, RP11‐343N15.5, and RP11‐479G22.8 were identified as the independent predictors of patients’ overall survival in HCC by sequential univariate Cox and 1000 times Cox LASSO regression with 10‐fold CV, and multivariate Cox analysis with 1000 times bootstrapping. In the Kaplan‐Meier analysis with patients trichotomized by the six‐lncRNA signature, high‐risk patients showed significantly shorter survival than mid‐ and low‐risk patients (log‐rank test P < 0.0001). According to the ROCs, the six‐lncRNA signature showed superior predictive capacity than the two existing four‐lncRNA combinations and the traditional prognostic clinicopathological parameter TNM stage. Furthermore, low MIR22HG and CTC‐297N7.9, but high CTD‐2139B15.2, RP11‐589N15.2, RP11‐343N15.5, and RP11‐479G22.8, were, respectively, demonstrated to be related with the malignant phenotypes of HCC. Functionally, the six lncRNAs were disclosed to involve in the regulation of multiple cell cycle and stress response‐related pathways via mediating transcription regulation and chromatin modification. In conclusion, our study identified a novel six‐lncRNA signature for resectable HCC prognosis prediction and indicated the underlying mechanisms of HCC progression and the potential functions of the six lncRNAs awaiting further elucidation.
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