The Mechanism and Clinical Significance of Circular RNAs in Hepatocellular Carcinoma.
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ABSTRACT:
SUBMITTER: Huang Z
PROVIDER: S-EPMC8445159 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Circular RNAs (circRNAs) are novel noncoding RNAs with covalently closed-loop structures that can regulate eukaryotic gene expression. Due to their stable structure, circRNAs are widely distributed in the cytoplasm and have important biological functions, including as microRNA sponges, RNA-binding protein conjugates, transcription regulators, and translation templates. Breast cancer is among the most common malignant cancers diagnosed in women worldwide. Despite the development of comprehensive treatments, breast cancer still has high mortality rates. Recent studies have unmasked critical roles for circRNAs in breast cancer as regulators of tumour initiation, progression, and metastasis. Further, research has revealed that some circRNAs have the potential for use as diagnostic and prognostic biomarkers in clinical practice. Herein, we review the biogenesis and biological functions of circRNAs, as well as their roles in different breast cancer subtypes. Moreover, we provide a comprehensive summary of the clinical significance of circRNAs in breast cancer. CircRNAs are believed to be a hot focus in basic and clinical research of breast cancer, and innovative future research directions of circRNAs could be used as biomarkers, therapeutic targets, or novel drugs.Abbreviations: CeRNA: Competitive endogenous RNA; ciRNA: Circular intronic RNA; circRNA: Circular RNA; EIciRNA: Exon-intron circRNA; EMT: Epithelial-mesenchymal transition; IRES: Internal ribosome entry site; lncRNA: Long non-coding RNA; miRNA: MicroRNA; MRE: MiRNA response element; ncRNA: Non-coding RNA; RBP: RNA-binding protein; RNA-seq: RNA sequencing; RT-PCR: Reverse transcription-polymerase chain reaction.
| S-EPMC10730165 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) ranks the third leading cause of cancer death in the world and has a notably low survival rate. Circular RNAs (circRNAs) are newly classed non-coding RNA (ncRNA) members that are capable of regulating gene expression at transcription or post-transcription levels. Recent studies demonstrate that some circRNAs are differentially expressed in HCC, and the deregulation of these circRNAs is associated with the clinical pathological and prognostic significance. They also play essential roles in HCC progression, and contribute to cell proliferation, migration, invasion and metastasis by targeting different microRNAs (miRNAs) and protein-coding genes. In this review, we concentrate on recent progress of some important circRNAs in HCC, with an emphasis on their deregulation, functions and regulatory mechanisms, and discuss their potential utility as diagnostic and/or prognostic biomarkers or therapeutic targets for HCC.
| S-EPMC5950583 | biostudies-literature
Project description:BackgroundHCC is one of the most common malignancies with an increasing incidence worldwide, especially in Asian countries. However, even though targeted cancer therapy drugs such as sorafenib and regorafenib are available, the overall outcome of HCC remains unsatisfactory. Thus, it is urgent to investigate the molecular mechanisms of HCC progression, so as to provide accurate diagnostic criteria and therapeutic targets.MethodsRNA-seq data was used to identify and quantify circular RNAs (circRNAs). DESeq2 was used to identify the differentially expressed circRNAs. miRNA binding sites within circRNAs were identified by miRanda. Gene set enrichment analysis (GSEA) was conducted to predict the biological function of circRNAs.ResultsThe differential expression analysis identified 107 upregulated and 95 downregulated circRNAs in HCC tissues. We observed that a differentially expressed circRNA (DE-circRNA), hsa_circ_0141900 was highly negatively correlated with its parental gene RAB1A (PCC < -0.6), which was also closely associated with mTOR signaling pathway. Moreover, we also constructed competing endogenous RNA (ceRNA) network to identify key circRNAs involved in HCC. Notably, hsa_circ_0002130 and hsa_circ_0008774 were highly correlated with the genes involved in gluconeogenesis and HNF3A pathway via the target genes, GOT2 and AR, suggesting that the two circRNAs might regulate these pathways, respectively. Survival analysis revealed that GOT2 was associated with favorable prognosis. Furthermore, high expression of hsa_circ_0002130 was found to inhibit tumor cell growth and promotes GOT2 expression.ConclusionIn summary, the circRNAs highlighted by the integrative analysis greatly improved our understanding of the underlying mechanism of circRNAs in HCC.
| S-EPMC8170000 | biostudies-literature
Project description:Circular RNAs (circRNAs) are covalently closed RNA molecules that play important regulatory roles in various tumors. Prostate cancer (PCa) is one of the most common malignant tumors in the world, with high morbidity and mortality. In recent years, more and more circRNAs have been found to be abnormally expressed and involved in the occurrence and development of PCa, including cell proliferation, apoptosis, invasion, migration, metastasis, chemotherapy resistance, and radiotherapy resistance. Most of the circRNAs regulate biological behaviors of cancer through a competitive endogenous RNA (ceRNA) regulatory mechanism, and some can exert their functions by binding to proteins. circRNAs are also associated with many clinicopathological features of PCa, including tumor grade, lymph node metastasis, and distant metastasis. In addition, circRNAs are potential diagnostic and prognostic biomarkers for PCa. Considering their critical regulatory roles in the progression of PCa, circRNAs would be the potential therapeutic targets. In this paper, the current research status of circRNAs in PCa is briefly reviewed.
| S-EPMC8585584 | biostudies-literature
Project description:Circular RNAs (circRNAs) are noncoding RNA molecules that display a perturbed arrangement of exons, called backsplicing. To examine the prognostic and biologic significance of circRNA expression in cytogenetically normal acute myeloid leukemia (CN-AML), we conducted whole-transcriptome profiling in 365 younger adults (age 18-60 years) with CN-AML. We applied a novel pipeline, called Massive Scan for circRNA, to identify and quantify circRNA expression. We validated the high sensitivity and specificity of our pipeline by performing RNase R treatment and RNA sequencing in samples of AML patients and cell lines. Unsupervised clustering analyses identified 3 distinct circRNA expression-based clusters with different frequencies of clinical and molecular features. After dividing our cohort into training and validation data sets, we identified 4 circRNAs (circCFLAR, circKLHL8, circSMC1A, and circFCHO2) that were prognostic in both data sets; high expression of each prognostic circRNA was associated with longer disease-free, overall, and event-free survival. In multivariable analyses, high circKLHL8 and high circFCHO2 expression were independently associated with better clinical outcome of CN-AML patients, after adjusting for other covariates. To examine the biologic relevance of circRNA expression, we performed knockdown screening experiments in a subset of prognostic and gene mutation-related candidate circRNAs. We identified circFBXW7, but not its linear messenger RNA, as a regulator of the proliferative capacity of AML blasts. In summary, our findings underscore the molecular associations, prognostic significance, and functional relevance of circRNA expression in CN-AML.
| S-EPMC6988408 | biostudies-literature
Project description:Objective: To enquire into the clinical significance and potential molecular mechanism of microRNA (miRNA)-196b-5p in hepatocellular carcinoma (HCC). Methods: Quantitative reverse transcription and polymerase chain reaction (qRT-PCR) were utilized to examine miR-196b-5p expression level in 67 HCC paraffin embedded tissues and corresponding adjacent tissues. Correlations of miR-196b-5p expression level with clinicopathological characteristics were analyzed in our study. The expression level and clinical significance of miR-196b-5p in HCC were also evaluated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We made predictions of the target genes of miR-196b-5p by twelve online software and then selected genes predicted by at least 5 software. Subsequently, in order to obtain the potential target genes of miR-196b-5p, we overlapped the predicted target genes and down-regulated mRNAs in HCC based on TCGA database. Then, we performed the Gene Ontology (GO) and the Disease Ontology (DO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Protein-Protein Interaction (PPI) network construction of those miR-196b-5p potential target genes. Results: Higher expression level of miR-196b-5p was seen in HCC tissues than in the corresponding adjacent tissues based on qRT-PCR (P = 0.0007). The expression level of miR-196b-5p was linked with tumor size (P = 0.03), tumor node (P = 0.024), vascular invasion (P = 0.029) and capsular invasion (P = 0.026) in HCC patients. Comprehensive meta-analysis of miR-196b-5p expression based on TCGA, GEO and qRT-PCR verified that higher expression level of miR-196b-5p was observed in HCC tissues than in normal control liver tissues (SMD = 0.56, 95%CI: 0.39-0.72, P heterogeneity = 0.275, I2 = 18.3%). GO annotation revealed that the top terms in biological process, cellular component and molecular function were single-organism catabolic process, neuronal cell body and transmembrane receptor protein kinase activity, respectively. The most relevant disease in DO annotation was arteriosclerosis. The tryptophan metabolism pathway ranked first in KEGG pathway enrichment analysis. The PPI network showed that IGF1, FOXO1, AR and FOS were mostly likely to become the core genes of miR-196b-5p potential target genes, which however required further experiments for validation. Conclusion: The miR-196b-5p was observed to show higher expression in HCC tissues than in normal control liver tissues. Moreover, the miR-196b-5p expression level had correlations with the clinicopathological parameters such as vascular invasion of HCC, but the molecular mechanisms of miR-196b-5p in HCC still need further elucidation and verification.
| S-EPMC6775707 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the most frequent malignancies, with high incidence and mortality. As the majority of HCC patients are diagnosed at an advanced stage and die of recurrence and metastasis, its pathology and new biomarkers are needed. Circular RNAs (circRNAs) are a large subclass of long non-coding RNAs (lncRNAs) with covalently closed loop structures and abundant, conserved, stable, tissue-specific expression in mammalian cells. CircRNAs exert multiple functions in HCC initiation, growth and progression, serving as promising biomarkers for diagnosis, prognosis and therapeutic targets for this disease. This review briefly describes the biogenesis and biological functions of circRNAs and elucidates the roles of circRNAs in the development and progression of HCC, especially regarding epithelial-mesenchymal transition (EMT), drug resistance and interactions with epigenetic modifications. In addition, this review highlights the implications of circRNAs as potential biomarkers and therapeutic targets for HCC. We hope to provide novel insight into the roles of circRNAs in HCC.
| S-EPMC9986438 | biostudies-literature
Project description:Background: Hepatocellular carcinoma (HCC), which is the most common type of primary liver cancer, often presents at advanced stage with a dismal prognosis. Novel tumor biomarkers are needed to aid in HCC early detection and prognostication. Methods: Immunohistochemical staining for RecQ-mediated genome instability protein 2 (RMI2) was performed in 330 surgically resected HCC specimens and 190 adjacent normal tissues. Univariate and multivariate regression analysis were applied to identify prognostic indicators of HCC outcomes. Patient's survival was assessed with the Kaplan-Meier method. Results: RMI2 in HCC tissue was significantly higher than that in adjacent normal tissues, and was positively correlated with HCC histological grade and stage (P < .05) but negatively correlated with the survival period. RIM2 was identified to be an independent prognostic indicator for HCC. Conclusion: The abnormal expression of RMI2 may be related to the occurrence and development of HCC. RIM2 could potentially serve as a novel tumor-specific biomarker for HCC diagnosis and prognosis prediction.
| S-EPMC8516379 | biostudies-literature
Project description:Recent findings from The Cancer Genome Atlas project have provided a comprehensive map of genomic alterations that occur in hepatocellular carcinoma (HCC), including unexpected mutations in apolipoprotein B (APOB). We aimed to determine the clinical significance of this non-oncogenetic mutation in HCC. An Apob gene signature was derived from genes that differed between control mice and mice treated with siRNA specific for Apob (1.5-fold difference; P < 0.005). Human gene expression data were collected from four independent HCC cohorts (n = 941). A prediction model was constructed using Bayesian compound covariate prediction, and the robustness of the APOB gene signature was validated in HCC cohorts. The correlation of the APOB signature with previously validated gene signatures was performed, and network analysis was conducted using ingenuity pathway analysis. APOB inactivation was associated with poor prognosis when the APOB gene signature was applied in all human HCC cohorts. Poor prognosis with APOB inactivation was consistently observed through cross-validation with previously reported gene signatures (NCIP A, HS, high-recurrence SNUR, and high RS subtypes). Knowledge-based gene network analysis using genes that differed between low-APOB and high-APOB groups in all four cohorts revealed that low-APOB activity was associated with upregulation of oncogenic and metastatic regulators, such as HGF, MTIF, ERBB2, FOXM1, and CD44, and inhibition of tumor suppressors, such as TP53 and PTEN. In conclusion, APOB inactivation is associated with poor outcome in patients with HCC, and APOB may play a role in regulating multiple genes involved in HCC development.
| S-EPMC6235894 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is currently still a major factor leading to death, lacking of reliable biomarkers. Therefore, deep understanding the pathogenesis for HCC is of great importance. The emergence of circular RNA (circRNA) provides a new way to study the pathogenesis of human disease. Here, we employed the prediction tool to identify circRNAs based on RNA-seq data. Then, to investigate the biological function of the circRNA, the candidate circRNAs were associated with the protein-coding genes (PCGs) by GREAT. We found significant candidate circRNAs expression alterations between normal and tumor samples. Additionally, the PCGs associated with these candidate circRNAs were also found have discriminative expression patterns between normal and tumor samples. The enrichment analysis illustrated that these PCGs were predominantly enriched for liver/cardiovascular-related diseases such as atherosclerosis, myocardial ischemia and coronary heart disease, and participated in various metabolic processes. Together, a further network analysis indicated that these PCGs play important roles in the regulatory and the PPI network. Finally, we built a classification model to distinguish normal and tumor samples by using candidate circRNAs and their associated genes, respectively. Both of them obtained satisfactory results (~ 0.99 of AUC for circRNA and PCG). Our findings suggested that the circRNA could be a critical factor in HCC, providing a useful resource to explore the pathogenesis of HCC.
| S-EPMC5367815 | biostudies-literature