• Circular
• LncRNAs
• MiRNAs
• Mitochondrial RNAs
• Noncoding RNAs
• PIWI-interacting RNAs
• Schistosoma haematobium
• SnoRNAs
• Urinary bladder cancer

• Humans
• Urinary Bladder Neoplasms/genetics
• Urinary Bladder Neoplasms/diagnosis
• Urinary Bladder Neoplasms/therapy
• Urinary Bladder Neoplasms/pathology
• RNA, Untranslated/genetics
• Prognosis
• Tumor Microenvironment/genetics
• Biomarkers, Tumor/genetics

• diagnostic biomarkers
• hepatocellular carcinoma
• liquid biopsy
• liver disease
• network meta-analysis

• actin‐like 6A
• circRNA
• epithelial‐mesenchymal transition
• hepatocellular carcinoma
• migration

• diagnosis and prognosis
• epigenetic factors
• hepatocellular carcinoma
• miRNA sponge
• therapy resistance

• Humans
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/diagnosis
• Liver Neoplasms/genetics
• Liver Neoplasms/therapy
• Liver Neoplasms/diagnosis
• Gene Expression Regulation, Neoplastic
• Prognosis
• Biomarkers, Tumor/genetics
• RNA, Untranslated/genetics
• RNA, Long Noncoding/genetics
• Animals
• MicroRNAs/genetics

• Circular RNA (circRNA)
• biomarker
• complications
• diabetes
• insulin

• Humans
• RNA, Circular/genetics
• RNA/genetics
• RNA/metabolism
• Diabetes Mellitus/genetics

• circular RNAs
• drug resistance
• epigenetic modifications
• functions
• hepatocellular carcinoma
• implications

• National Natural Science Foundation of China

• alpha-fetoprotein
• biomarker
• circulating nucleic acids
• circulating tumor cells
• exosomes
• hepatocellular carcinoma
• liquid biopsy
• personalized medicine

• Circular RNA
• Hepatitis B virus
• Hepatocellular carcinoma
• Serum biomarker
• mRNA

• Biomarkers
• Circular RNAs
• Diagnosis
• Function
• Hepatocellular carcinoma
• Targeted therapy

Circular RNA (circRNA), a new type of endogenous non-coding RNA, is abundantly present in eukaryotic cells, and characterized as stable high conservation and tissue specific expression. It has been generated increasing attention because of their close association with the progress of diseases. The liver is the vital organ of humans, while it is prone to acute and chronic diseases due to the influence of multiple pathogenic factors. Moreover, hepatocellular carcinoma (HCC) is the one of most common cancer and the leading cause of cancer death worldwide. Overwhelming evidences indicate that some circRNAs are differentially expressed in liver diseases, such as, HCC, chronic hepatitis B, hepatic steatosis and hepatoblastoma tissues, etc. Additionally, these circRNAs are related to proliferation, invasion, migration, angiogenesis, apoptosis, and metastasis of cell in liver diseases and act as oncogenic agents or suppressors, and linked to clinical manifestations. In this review, we briefly summarize the biogenesis, characterization and biological functions, recent detection and identification technologies of circRNA, and regulation network mechanism of circRNA in liver diseases, and discuss their potential values as biomarkers or therapeutic targets for liver diseases, especially on HCC.

• Biomarker
• Hepatocellular carcinoma (HCC)
• Liver diseases
• circRNA
• miRNA sponge

Liver cancer is the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) accounts for about 85%-90% of all primary liver malignancies. However, only 20-30% of HCC patients are eligible for curative therapy mainly due to the lack of early-detection strategies, highlighting the significance of reliable and accurate biomarkers. The integration of multi-omics became an important tool for biomarker screening and unique alterations in tumor-associated genes, transcripts, proteins, post-translational modifications and metabolites have been observed. We here summarized the novel biomarkers for HCC diagnosis based on multi-omics technology as well as the clinical significance of these potential biomarkers in the early detection of HCC.

• Science and Technology Commission of Shanghai Municipality

• ASO, antisense oligonucleotide
• CCA, cholangiocarcinoma
• CLIP, cross-linking immunoprecipitation
• EMT, epithelial-to-mesenchymal transition
• EVs, extracellular vesicles
• HCC, hepatocellular carcinoma
• HN1, haematopoietic- and neurologic-expressed sequence 1
• IRES, internal ribosome entry sites
• NGS, next-generation sequencing
• QKI, Quaking
• RBP, RNA-binding protein
• RISC, RNA-induced silencing complex
• TAM, tumour-associated macrophage
• TSB, target site blockers
• biomarker
• cancer hallmarks
• cholangiocarcinoma
• circRNA
• circRNA, circular RNA
• hepatocellular carcinoma
• miRNA, microRNA
• shRNA, small-hairpin RNA
• snRNP, small nuclear ribonuclear proteins

The lack of accurate biomarkers impeded the screening, diagnosis and early treatment of hepatocellular carcinoma (HCC). As a result of the development of high-throughput transcriptome analysis techniques, circular RNAs, a newly discovered class of noncoding RNAs, were recognized as potential novel biomarkers. This meta-analysis was performed to update the diagnostic roles of circular RNAs for HCC. We acquired 23 articles from PubMed, Web of Science, EMBASE, and Cochrane Library databases up to September 2021. The overall sensitivity was 0.80 (95% CI: 0.77–0.84), and the specificity was 0.83 (95% CI: 0.79–0.85), with an AUC of 0.88 (0.85–0.91). Considering of the significant heterogeneity, studies were divided into four groups based on the control types. The circular RNAs in exosomes had a sensitivity of 0.69 (95% CI: 0.61–0.75), and a highest specificity of 0.91 (95% CI: 0.83–0.96). The pooled sensitivity of circular RNAs in serum/plasma was 0.84 (95% CI: 0.81–0.87), and the pooled specificity was 0.83 (95% CI: 0.79–0.86). The pooled sensitivity of circular RNAs distinguishing tumor tissue from chronic hepatitis/cirrhosis tissues was 0.56 (95% CI: 0.48–0.64), and specificity was 0.76 (95% CI: 0.67–0.82). When the controls were adjacent tissues, the sensitivity was 0.78 (95% CI: 0.70–0.84), and the specificity was 0.78 (95% CI: 0.71–0.85). Hsa_circ_0001445 with a pooled sensitivity of 0.81, a specificity of 0.76 and an AUC of 0.85 in two studies, might be a suitable diagnostic blood biomarker for HCC. Relying on function in HCC, the AUC of subgroups were 0.88 (95%CI: 0.84–0.90) (function group) and 0.87 (95%CI: 0.84–0.90) (unknown function group). As for only reported in HCC or not, these circular RNAs had an AUC of 0.89 (95%CI: 0.86–0.91) (only in HCC) and 0.85 (95%CI: 0.82–0.88) (not only in HCC). In conclusion, the results suggested that circular RNAs were acceptable biomarkers for detecting HCC, especially those circular RNAs existing in exosomes or serum/plasma.

• circular RNAs
• diagnosis
• exosome
• hepatocellular carcinoma
• meta-analysis
• serum/plasma

• biomarkers
• diagnostic
• hepatocellular carcinoma (HCC)
• network meta-analysis

• Biomarkers, Tumor/genetics
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/genetics
• Humans
• Liver Neoplasms/diagnosis
• Liver Neoplasms/genetics
• Publication Bias
• RNA, Neoplasm/genetics
• RNA, Neoplasm/metabolism

• AGO2
• CircRNAs
• Circular RNA
• Pipeline
• RNA metabolism
• Splicing

• Animals
• Argonaute Proteins/metabolism
• Brain/metabolism
• Databases, Nucleic Acid
• Exoribonucleases
• Genomics
• Humans
• Mice
• Molecular Sequence Annotation
• RNA, Circular/analysis
• RNA, Circular/genetics
• RNA, Circular/metabolism
• RNA-Seq
• Rats
• Software

• R01 AG057700 NIA NIH HHS
• R01 GM124406 NIGMS NIH HHS
• Michael J. Fox Foundation for Parkinson's Research

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. In view of the lack of early obvious clinical symptoms and related early diagnostic biomarkers with high specificity and sensitivity, most HCC patients are already at the advanced stages at the time of diagnosis, and most of them are accompanied by distant metastasis. Furthermore, the unsatisfactory effect of the follow-up palliative care contributes to the poor overall survival of HCC patients. Therefore, it is urgent to identify effective early diagnosis and prognostic biomarkers and to explore novel therapeutic approaches to improve the prognosis of HCC patients. Circular RNA (CircRNA), a class of plentiful, stable, and highly conserved ncRNA subgroup with the covalent closed loop, is dysregulated in HCC. Increasingly, emerging evidence have confirmed that dysregulated circRNAs can regulate gene expression at the transcriptional or post-transcriptional level, mediating various malignant biological behaviors of HCC cells, including proliferation, invasion, metastasis, immune escape, stemness, and drug resistance, etc.; meanwhile, they are regarded as potential biomarkers for early diagnosis and prognostic evaluation of HCC. This article reviews the research progress of circRNAs in HCC, expounding the potential molecular mechanisms of dysregulated circRNAs in the carcinogenesis and development of HCC, and discusses those application prospects in the diagnosis and prognosis of HCC.

• biomarker
• circular RNAs
• diagnosis
• hepatocellular carcinoma
• prognosis
• sponge

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Due to the lack of potent diagnosis and prognosis biomarkers and effective therapeutic targets, the overall prognosis of survival is poor in HCC patients. Circular RNAs (circRNAs) are a class of novel endogenous non-coding RNAs with covalently closed loop structures and implicated in diverse physiological processes and pathological diseases. Recent studies have demonstrated the involvement of circRNAs in HCC diagnosis, prognosis, development, and drug resistance, suggesting that circRNAs may be a class of novel targets for improving HCC diagnosis, prognosis, and treatments. In fact, some artificial circRNAs have been engineered and showed their therapeutic potential in treating HCV infection and gastric cancer. In this review, we introduce the potential of circRNAs as biomarkers for HCC diagnosis and prognosis, as therapeutic targets for HCC treatments and discuss the challenges in circRNA research and chances of circRNA application.

• biomarkers for diagnosis and prognosis
• circular RNAs
• drug resistance
• hepatocellular carcinoma
• oncogenic circRNAs
• tumor suppressive circRNAs

• Abdomen/diagnostic imaging
• Adult
• Bias
• Biomarkers, Tumor/blood
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/pathology
• Case-Control Studies
• Chronic Disease
• Confidence Intervals
• Cross-Sectional Studies
• Female
• Humans
• Liver Diseases/complications
• Liver Neoplasms/blood
• Liver Neoplasms/diagnosis
• Liver Neoplasms/pathology
• Male
• Sensitivity and Specificity
• Ultrasonography/methods
• alpha-Fetoproteins/analysis

• Acetylaminofluorene
• Apoptosis
• Autophagy
• Diethylnitrosamine
• Hepatic precancerous lesion
• MicroRNA

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has high mortality. Biomarkers related to HCC, such as alpha-fetoprotein, and imaging technology, such as ultrasound and computed tomography, have been used to screen and monitor HCC, but HCC is still difficult to diagnose effectively in the early stage due to the low sensitivity of the above mentioned traditional methods. There is an urgent need for noninvasive biomarkers to facilitate the screening and early diagnosis of HCC. With the advancement of next-generation sequencing, genetic biomarkers are becoming the core of cancer diagnosis. Genetic biomarkers such as peripheral blood circulating tumor DNA, microRNAs, long noncoding RNAs, circular RNAs, and exosomes have become the focus of early HCC diagnostics. HCC genetic biomarkers have been implemented in clinical practice. In this review, we describe the available literature on peripheral blood genetic biomarkers in the diagnosis of early HCC.

• biomarkers
• exosome
• hepatocellular carcinoma
• microRNA
• nucleic acid

• biological function
• biomarker
• circular RNAs
• drug resistance
• hepatocellular carcinoma
• treatment

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumour, which has posed a heavy health and financial burden worldwide. Due to limited symptoms at the early stage and the limitation in current biomarkers, HCC patients are usually diagnosed at the advanced stage with a pessimistic overall survival rate. Circular RNAs (circRNAs) are a subclass of single‐stranded RNAs characterized by a covalently closed loop structure without 3’‐ or 5’‐end. With advances in high‐throughput sequencing technology and bioinformatics, accumulating studies have demonstrated the promotor or suppressor roles of circRNAs in the carcinogenesis, progression, and metastasis of HCC. Moreover, circRNAs are characteristic of higher abundance, stability and conservation compared with linear RNAs. Therefore, circRNAs have emerged as one of the most promising diagnostic and prognostic biomarkers for HCC with reliable accuracy, sensitivity and specificity. In this review, we briefly introduce the characteristics of circRNAs and summarize the roles of circRNAs in the biological procedures of HCC. Furthermore, we provide an overview on the potential diagnostic and prognostic value of circRNAs as biomarkers for patients with HCC. Finally, we discuss future perspectives of circRNAs in cancer research.

• circular RNAs
• diagnostic biomarker
• hepatocellular carcinoma
• prognostic biomarker

Exosomes play crucial roles in regulating the crosstalk between normal and cancer cells in the tumor microenvironment, and in regulating cancer proliferation, migration and invasion through their cargo molecules.

We analyzed the pro-invasiveness of exosomal circRNA-100,338 in HCC using the transwell invasion assay. The co-culture of human umbilical vein endothelial cells (HUVEC) and exosomes derived from HCC cell lines were used to evaluate the impact of HCC derived exosomes on HUVEC. Nude mice models were used to validate the findings in vitro. Clinically, quantitative RT-PCR was used to quantify the expression of serum exosomal circRNA-100,338 in HCC patients at both pre-surgery within one week and post-surgery within three weeks.

We aim to investigate the pro-invasive role of exosomal circRNA-100,338 in HCC metastasis. We for the first time demonstrated that circRNA-100,338 was highly expressed in both highly metastatic HCC cells and their secreted exosomes. The transwell invasion assay showed that the overexpression or knockdown of exosomal circRNA-100,338 significantly enhanced or reduced the invasive abilities of HCC cells. Subsequently, in vitro and in vivo assays showed that exosomal circRNA-100,338 affected the cell proliferation, angiogenesis, permeability, and vasculogenic mimicry (VM) formation ability of human umbilical vein endothelial cells (HUVEC), and tumor metastasis. Furthermore, we also observed that the persistent high expression of exosomal circRNA-100,338 in serum of HCC patients who underwent curative hepatectomy may be a risk indicator of pulmonary metastasis and poor survival.

Our findings indicated that metastatic ability of HCC cells could be enhanced by transferring exosomal circRNA-100,338 to recipient HUVECs, which could affect proangiogenic activity by regulating angiogenesis.

• Angiogenesis
• CircRNA-100,338
• Exosome
• Hepatocellular carcinoma (HCC)
• Tumor metastasis

Circular RNAs (circRNAs) have been increasingly demonstrated to function as novel promising therapeutic RNA molecules for diverse human diseases, including cancer. Although the important role of circRNAs has been well documented in HCC, the complex mechanisms of circRNAs in HCC need to be elucidated. Here, a novel circRNA circ_0001955 was identified from three GSE datasets (GSE7852, GSE94508, and GSE97322) as a differentially expressed circRNA between HCC and normal samples. We revealed that circ_0001955, TRAF6 and MAPK11 levels were increased, while miR-516a-5p levels were decreased in HCC tumor tissues compared to adjacent normal tissues. Knockdown of circ_0001955 repressed HCC tumor growth in vitro and in vivo, while overexpression of circ_0001955 exhibited the opposite effect. Circ_0001955 was identified as a sponge for miR-145-5p and miR-516a-5p, and TRAF6 and MAPK11 were demonstrated to be two target genes of miR-516a-5p. In conclusion, circ_0001955 facilitated HCC tumorigenesis by sponging miR-516a-5p to release TRAF6 and MAPK11 expression.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and a leading cause of cancer-related deaths worldwide. Emerging studies have shown that circular RNAs (circRNAs) are differentially expressed in HCC and play an important role in HCC pathogenesis and metastasis. However, the mechanism of circRNA in the chemoresistance of HCC remains unclear. In this study, we aimed to investigate the role of circRNA in cisplatin resistance of HCC. We identified a novel circRNA circRNA_101505 that was decreased in cisplatin-resistant HCC tissues and cell lines, and associated with a poor survival outcome. Gain-of-function investigations showed that overexpression of circRNA_101505 suppressed cancer cell growth in vivo and in vitro, and enhanced cisplatin toxicity in HCC cells. Mechanistic studies found that circRNA_101505 could sensitize HCC cells to cisplatin by sponging miR-103, and thereby promoting oxidored-nitro domain-containing protein 1 (NOR1) expression. In conclusion, the significant inhibitory effects indicate circRNA_101505 to be a potential therapeutic target for HCC treatment. Our findings provide significant evidence to further elucidate the therapeutic use of circRNA in HCC.

• Cancer therapy
• Tumour-suppressor proteins

• Circular RNA
• Diagnostic biomarker
• Hepatocellular carcinoma
• Prognostic biomarker
• Therapeutic target
• miRNA sponge

• circRNA
• community-acquired pneumonia
• diagnostic biomarker

• circ_0000267
• circular RNA
• hepatocellular carcinoma
• miR-646
• prognosis