Abstract
Background: Circular RNAs (circRNAs) have been demonstrated to be closely related to the carcinogenesis of human cancer in recent years. However, the molecular mechanism of circRNAs in the pathogenesis of hepatocellular carcinoma (HCC) has not been fully elucidated. We aimed to identify critical circRNAs and explore their potential regulatory network in HCC. Methods: The robust rank aggregation (RRA) algorithm and weighted gene co-expression network analysis (WGCNA) were conducted to unearth the differentially expressed circRNAs (DEcircRNAs) in HCC. The expression levels of DEcircRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). A circRNA-miRNA-mRNA regulatory network was constructed by computational biology, and protein-protein interaction (PPI) network, functional enrichment analysis, survival analysis, and infiltrating immune cells analysis were performed to uncover the potential regulatory mechanisms of the network. Results: A total of 22 DEcircRNAs were screened out from four microarray datasets (GSE94508, GSE97332, GSE155949, and GSE164803) utilizing the RRA algorithm. Meanwhile, an HCC-related module containing 404 circRNAs was identified by WGCNA analysis. After intersection, only four circRNAs were recognized in both algorithms. Following qRT-PCR validation, three circRNAs (hsa_circRNA_091581, hsa_circRNA_066568, and hsa_circRNA_105031) were chosen for further analysis. As a result, a circRNA-miRNA-mRNA network containing three circRNAs, 17 miRNAs, and 222 mRNAs was established. Seven core genes (ESR1, BUB1, PRC1, LOX, CCT5, YWHAZ, and DDX39B) were determined from the PPI network of 222 mRNAs, and a circRNA-miRNA-hubgene network was also constructed. Functional enrichment analysis suggested that these seven hub genes were closely correlated with several cancer related pathways. Survival analysis revealed that the expression levels of the seven core genes were significantly associated with the prognosis of HCC patients. In addition, we also found that these seven hub genes were remarkably related to the infiltrating levels of immune cells. Conclusion: Our research identified three pivotal HCC-related circRNAs and provided novel insights into the underlying mechanisms of the circRNA-miRNA-mRNA regulatory network in HCC.
Highlights
Primary liver cancer is a common malignant tumour and the third leading cause of cancer-related deaths worldwide, threatening our health and life
Our study showed that five upregulated hub genes, BUB1, PRC1, LOX, CCT5, and YWHAZ, had positive relationships with immune cells infiltration levels
We found that DDX39B was upregulated in Hepatocellular carcinoma (HCC) tissues and high DDX39B expression was correlated to poor overall survival (OS) and disease-free survival (DFS) in HCC patients based on the the Cancer Genome Atlas (TCGA) database
Summary
Primary liver cancer is a common malignant tumour and the third leading cause of cancer-related deaths worldwide, threatening our health and life. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for 75–80% of cases (Sung et al, 2021). With the recent developments in highthroughput sequencing technology, circRNAs have been found to be closely related to many human diseases including cancer, cardiovascular diseases, autoimmune diseases, Alzheimer’s disease, and so on (Meng et al, 2017; Altesha et al, 2019; Zhou et al, 2019; Huang J.-L. et al, 2020). Circular RNAs (circRNAs) have been demonstrated to be closely related to the carcinogenesis of human cancer in recent years. The molecular mechanism of circRNAs in the pathogenesis of hepatocellular carcinoma (HCC) has not been fully elucidated. Gene Ontology protein kinase binding lung development nucleoplasm protein binding KEGG PATHWAY Cell cycle Oocyte meiosis Reactome.
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