Abstract
Although huge progress has been made in therapeutics against hepatocellular carcinoma (HCC) over the decades, the prognosis of this lethal disease remains poor. To find out risk factors for HCC-related outcome and better predict the prognosis, there is an unmet need to identify novel biomarkers of HCC. Accumulating evidence suggests that circRNAs play pivotal roles in carcinogenesis of several malignancies. In this study, we analyzed two datasets (GSE 94508 and GSE 97332) to examine differentially expressed circRNAs markedly related to HCC pathogenesis. Using Limma package in R and WGCNA analysis, hsa_circ_0000517 was significantly up-regulated in HCC (adjusted P < 0.01). Thereafter, a hsa_circ_0000517-related regulatory network was built based on application of databases including CSCD, TargetScan, miRDB, and miRTarBase. We uncovered the potential function of hsa_circ_0000517 through bioinformatics approaches, such as PPI network, GO, and KEGG pathway analyses. Specifically, functional analysis unveiled that hsa_circ_0000517 was likely to regulate the MAPK and Ras pathway through sponging several miRNAs and having an impact on the expression of TP53, MYC, and AKT1. To verify our initial finding, the expression of hsa_circ_0000517 in 60 HCC patients was detected by qRT-PCR and the expression in cancer tissues was higher compared with the paracarcinoma tissues. Survival analysis suggests high hsa_circ_0000517 expression was associated with adverse prognosis in HCC patients. Furthermore, this circRNA was significantly up-regulated in worse TNM stage, consistent with the progressive-stage-specific characteristic of circRNAs. A prognostic nomogram built on AFP and has_circ_0000517 showed significant diagnostic value. In all, we concluded that hsa_circ_0000517, a promising molecular in underlying mechanism of HCC, is a potent valuable biomarker for prognosis prediction.
Highlights
Hepatocellular carcinoma (HCC) is one of the most fatal carcinomas with relatively high mortality [1]
Prior studies have demonstrated that circRNAs are correlated with cancers, including gastric cancer, colorectal cancer, ovarian cancer, and hepatocellular carcinoma (HCC) [5,6,7]
A micro-array search of circular RNA in HCC was conducted in the Gene Expression Omnibus (GEO) database with the following keywords: (“circRNA” and “liver cancer”), we could find out two datasets: GSE 94508 and GSE 97332
Summary
Hepatocellular carcinoma (HCC) is one of the most fatal carcinomas with relatively high mortality [1]. There is an unmet need to develop effective biomarkers for diagnosis and prognosis of HCC. Circular RNAs (circRNAs), characterized by stable circular structure and sponge function in most cells, have been identified as one kind of novel and important regulatory non-coding RNAs (ncRNA). Given that circRNA expression shows high heterogeneity among different cells, tissues, and even the stages of disease, this kind of ncRNA has been considered as a latent diagnostic and prognostic biomarker and promising target for developing new therapeutic options against human malignant cancers [4]. CircRNAs have been reported to function as miRNA sponges with the competence of regulating miRNA via miRNA-targeted mRNAs repression since they were first studied [8]. The underlying function of most circRNAs and their mechanism in diseases are not completely known [9, 10]
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