Dataset Information

Genome-Wide Screening Identifies Prognostic Long Noncoding RNAs in Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis. Therefore, there is an urgent call for the investigation of novel biomarkers in HCC. In the present study, we identified 6 upregulated lncRNAs in HCC, including LINC01134, RHPN1-AS1, NRAV, CMB9-22P13.1, MKLN1-AS, and MAPKAPK5-AS1. Higher expression of these lncRNAs was correlated to a more advanced cancer stage and a poorer prognosis in HCC patients. Enrichment analysis revealed that these lncRNAs played a crucial role in HCC progression, possibly through a series of cancer-related biological processes, such as cell cycle, DNA replication, histone acetyltransferase complex, fatty acid oxidation, and lipid modification. Moreover, competing endogenous RNA (ceRNA) network analysis revealed that these lncRNAs could bind to certain miRNAs to promote HCC progression. Loss-of-function assays indicated that silencing of RHPN1-AS1 significantly suppressed HCC proliferation and migration. Though further validations are still needed, these identified lncRNAs could serve as valuable potential biomarkers for HCC prognosis.

SUBMITTER: Feng Y

PROVIDER: S-EPMC8163536 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Genome-Wide Screening Identifies Prognostic Long Noncoding RNAs in Hepatocellular Carcinoma.

Feng Yujie Y Hu Xiao X Ma Kai K Zhang Bingyuan B Sun Chuandong C

BioMed research international 20210520

Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis. Therefore, there is an urgent call for the investigation of novel biomarkers in HCC. In the present study, we identified 6 upregulated lncRNAs in HCC, including LINC01134, RHPN1-AS1, NRAV, CMB9-22P13.1, MKLN1-AS, and MAPKAPK5-AS1. Higher expression of these lncRNAs was correlated to a more advanced cancer stage and a poorer prognosis in HCC patients. Enrichment analysis revealed that these lncRNAs played a crucial role ...[more]

PMID: 34095306

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Project description:Background & aimsLong noncoding RNAs (lncRNAs) are found to have profound impacts on diverse cellular processes. Although high-throughput sequencing studies have shown the differential lncRNA expression profiles between hepatocellular carcinoma (HCC) and nontumor livers, the functional impacts of lncRNAs on HCC development await further investigation. Herein, we sought to address the functional roles of lncRNAs in HCC pathogenesis by in vivo functional screening.MethodsWe performed genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/dead CRISPR-associated protein 9 (dCas9) lncRNA activation screening in HCC xenografts. We characterized the clinical relevance of positively selected lncRNAs using transcriptomic data sets. We used CRISPR-based gene activation and knockdown approaches to show the functional roles of positively selected lncRNAs including Cancer Susceptibility 11 (CASC11) in HCC. RNA sequencing and chromatin isolation by RNA purification sequencing were used to investigate the molecular mechanisms of CASC11 in HCC progression.ResultsThe in vivo functional screening identified 1603 positively selected lncRNAs, 538 of which were overexpressed in HCC patients. Systematic transcriptomic data analysis and clinical investigation showed that patients with high expression of these lncRNA candidates correlated with aggressive tumor behaviors. Overexpression of these lncRNAs aggravated HCC cell growth. Detailed characterization of a lncRNA candidate, CASC11, showed its pivotal role in cell proliferation and tumor growth. Mechanistically, chromatin isolation by RNA purification sequencing showed that CASC11 was bound to the CASC11/MYC proto-oncogene shared promoter region on chromosome 8q24. CASC11 modulated the transcriptional activity of MYC in a cis-regulatory manner, which affected the expression of MYC downstream target genes, consequently promoting G1/S progression.ConclusionsOur study showed the power of in vivo CRISPR screening, which comprehensively investigated the functionality of lncRNAs in HCC progression, providing a rationale for targeting these lncRNAs clinically.

Project description:AbstractReliable biomarkers are of great significance for the treatment and diagnosis of hepatocellular carcinoma (HCC). This study identified potential prognostic epithelial-mesenchymal transition related lncRNAs (ERLs) by the cancer genome atlas (TCGA) database and bioinformatics.The differential expression of long noncoding RNA (lncRNA) was obtained by analyzing the lncRNA data of 370 HCC samples in TCGA. Then, Pearson correlation analysis was carried out with EMT related genes (ERGs) from molecular signatures database. Combined with the univariate Cox expression analysis of the total survival rate of hepatocellular carcinoma (HCC) patients, the prognostic ERLs were obtained. Then use "step" function to select the optimal combination of constructing multivariate Cox expression model. The expression levels of ERLs in HCC samples were verified by real-time quantitative polymerase chain reaction.Finally, we identified 5 prognostic ERLs (AC023157.3, AC099850.3, AL031985.3, AL365203.2, CYTOR). The model showed that these prognostic markers were reliable independent predictors of risk factors (P value <.0001, hazard ratio [HR] = 2.400, 95% confidence interval [CI] = 1.667-3.454 for OS). In the time-dependent receiver operating characteristic analysis, this prognostic marker is a good predictor of HCC survival (area under the curve of 1 year, 2 years, 3 years, and 5 years are 0.754, 0.720, 0.704, and 0.662 respectively). We analyzed the correlation of clinical characteristics of these prognostic markers, and the results show that this prognostic marker is an independent factor that can predict the prognosis of HCC more accurately. In addition, by matching with the Molecular Signatures Database, we obtained 18 ERLs, and then constructed the HCC prognosis model and clinical feature correlation analysis using 5 prognostic ERLs. The results show that these prognostic markers have reliable independent predictive value. Bioinformatics analysis showed that these prognostic markers were involved in the regulation of EMT and related functions of tumor occurrence and migration.Five prognostic types of ERLs identified in this study can be used as potential biomarkers to predict the prognosis of HCC.

Dataset Information

Genome-Wide Screening Identifies Prognostic Long Noncoding RNAs in Hepatocellular Carcinoma.

Publications

Genome-Wide Screening Identifies Prognostic Long Noncoding RNAs in Hepatocellular Carcinoma.

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