Circular RNAs in Hepatocellular Carcinoma: Emerging Functions to Clinical Significances

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and carries high morbidity and mortality. Diagnosing HCC at an early stage is challenging. Therefore, finding new, highly sensitive and specific diagnostic biomarkers for the diagnosis and prognosis of HCC patients is extremely important. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently closed loop structures. They are characterized by remarkable stability, long half-life, abundance and evolutionary conservation. Recent studies have shown that many circRNAs are expressed aberrantly in HCC tissues and have important regulatory roles during the development and progression of HCC. Hence, circRNAs are promising biomarkers for the diagnosis and prognosis of HCC. This review: (i) summarizes the biogenesis, categories, and functions of circRNAs; (ii) focuses on current progress of dysregulated expression of circRNAs in HCC with regard to regulation of the tumor hallmarks, “stemness” of cancer cells, and immunotherapy; (iii) highlights circRNAs as potential biomarkers and therapeutic targets for HCC; and (iv) discusses some of the challenges, questions and future perspectives of circRNAs research in HCC.

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Circular RNAs and Hepatocellular Carcinoma: New Epigenetic Players With Diagnostic and Prognostic Roles

Frontiers in Oncology ◽

10.3389/fonc.2021.653717 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kedeerya Aishanjiang ◽

Xin-dong Wei ◽

Yi Fu ◽

Xinjie Lin ◽

Yujie Ma ◽

...

Keyword(s):

Gastric Cancer ◽

Hepatocellular Carcinoma ◽

Closed Loop ◽

Therapeutic Potential ◽

Therapeutic Targets ◽

Circular Rnas ◽

Diagnosis And Prognosis ◽

Physiological Processes ◽

Non Coding Rnas ◽

Novel Targets

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.

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Circular RNAs Sparkle in the Diagnosis and Theranostics of Hepatocellular Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2020.628655 ◽

2021 ◽

Vol 11 ◽

Author(s):

Menglan Wang ◽

Minjie Wu ◽

Tian Xie ◽

Jianxiang Chen

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Diagnosis ◽

Potential Application ◽

Body Fluid ◽

Closed Loop ◽

High Specificity ◽

Host Gene ◽

Circular Rnas ◽

Scientific Interest ◽

Non Coding Rnas

Exonic circular RNAs (circRNAs) are a novel subgroup of non-coding RNAs, which are generated by a back-splicing mechanism of the exons or introns. Unlike the linear RNA, circRNA forms a covalently closed loop, and it normally appears more abundant than the linear products of its host gene. Due to the relatively high specificity and stability of circular RNAs in tissues and body fluid, circular RNAs have attracted widely scientific interest for its potential application in cancer diagnosis and as a guide for preclinical therapy, especially for hard-to-treat cancers with high heterogeneity, such as hepatocellular carcinoma (HCC). Thus, we summarize the updated knowledge of circular RNAs, including the mechanism of the generation of endogenous circular RNAs and their regulatory, diagnostic, and therapeutic roles in HCC.

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Tumor-Derived Exosomal Non-Coding RNAs: The Emerging Mechanisms and Potential Clinical Applications in Breast Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.738945 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yi Yi ◽

Min Wu ◽

Hong Zeng ◽

Weijie Hu ◽

Chongru Zhao ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Circular Rnas ◽

Diagnostic Biomarkers ◽

Diagnosis And Prognosis ◽

Regulated Expression ◽

Non Coding Rnas ◽

And Migration ◽

Novel Therapeutic Strategies ◽

Exosomal Mirna

Breast cancer (BC) is the most frequent malignancy and is ranking the leading cause of cancer-related death among women worldwide. At present, BC is still an intricate challenge confronted with high invasion, metastasis, drug resistance, and recurrence rate. Exosomes are membrane-enclosed extracellular vesicles with the lipid bilayer and recently have been confirmed as significant mediators of tumor cells to communicate with surrounding cells in the tumor microenvironment. As very important orchestrators, non-coding RNAs (ncRNAs) are aberrantly expressed and participate in regulating gene expression in multiple human cancers, while the most reported ncRNAs within exosomes in BC are microRNAs (miRNAs), long-noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). Notably, ncRNAs containing exosomes are novel frontiers to shape malignant behaviors in recipient BC cells such as angiogenesis, immunoregulation, proliferation, and migration. It means that tumor-derived ncRNAs-containing exosomes are pluripotent carriers with intriguing and elaborate roles in BC progression via complex mechanisms. The ncRNAs in exosomes are usually excavated based on specific de-regulated expression verified by RNA sequencing, bioinformatic analyses, and PCR experiments. Here, this article will elucidate the recent existing research on the functions and mechanisms of tumor-derived exosomal miRNA, lncRNA, circRNA in BC, especially in BC cell proliferation, metastasis, immunoregulation, and drug resistance. Moreover, these tumor-derived exosomal ncRNAs that existed in blood samples are proved to be excellent diagnostic biomarkers for improving diagnosis and prognosis. The in-depth understanding of tumor-derived exosomal ncRNAs in BC will provide further insights for elucidating the BC oncogenesis and progress and exploring novel therapeutic strategies for combating BC.

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Biomarkers (mRNAs and Non-Coding RNAs) for the Diagnosis and Prognosis of Colorectal Cancer – From the Body Fluid to Tissue Level

Frontiers in Oncology ◽

10.3389/fonc.2021.632834 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jinhua He ◽

Feifeng Wu ◽

Zeping Han ◽

Min Hu ◽

Weida Lin ◽

...

Keyword(s):

Colorectal Cancer ◽

Body Fluid ◽

Early Stage ◽

Tissue Level ◽

Carbohydrate Antigen ◽

The Body ◽

Circular Rnas ◽

Diagnosis And Prognosis ◽

Non Coding Rnas ◽

Low Sensitivity

In recent years, the diagnosis and treatment of colorectal cancer (CRC) have been continuously improved, but the mortality rate continues to be high, especially in advanced patients. CRC patients usually have no obvious symptoms in the early stage and are already in the advanced stage when they are diagnosed. The 5-year survival rate is only 10%. The blood markers currently used to screen for CRC, such as carcinoembryonic antigen and carbohydrate antigen 19-9, have low sensitivity and specificity, whereas other methods are invasive or too expensive. As a result, recent research has shifted to the development of minimally invasive or noninvasive biomarkers in the form of body fluid biopsies. Non-coding RNA molecules are composed of microRNAs, long non-coding RNAs, small nucleolar RNAs, and circular RNAs, which have important roles in the occurrence and development of diseases and can be utilized for the early diagnosis and prognosis of tumors. In this review, we focus on the latest findings of mRNA-ncRNA as biomarkers for the diagnosis and prognosis of CRC, from fluid to tissue level.

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Identification of BHLHE40 expression in peripheral blood mononuclear cells as a novel biomarker for diagnosis and prognosis of hepatocellular carcinoma

Scientific Reports ◽

10.1038/s41598-021-90515-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Pattapon Kunadirek ◽

Chaiyaboot Ariyachet ◽

Supachaya Sriphoosanaphan ◽

Nutcha Pinjaroen ◽

Pongserath Sirichindakul ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Early Stage ◽

High Sensitivity ◽

Peripheral Blood Mononuclear ◽

Diagnosis And Prognosis ◽

Transcription Profiles ◽

Blood Mononuclear Cells

AbstractNovel and sensitive biomarkers is highly required for early detection and predicting prognosis of hepatocellular carcinoma (HCC). Here, we investigated transcription profiles from peripheral blood mononuclear cells (PBMCs) of 8 patients with HCC and PBMCs from co-culture model with HCC using RNA-Sequencing. These transcription profiles were cross compared with published microarray datasets of PBMCs in HCC to identify differentially expressed genes (DEGs). A total of commonly identified of 24 DEGs among these data were proposed as cancer-induced genes in PBMCs, including 18 upregulated and 6 downregulated DEGs. The KEGG pathway showed that these enriched genes were mainly associated with immune responses. Five up-regulated candidate genes including BHLHE40, AREG, SOCS1, CCL5, and DDIT4 were selected and further validated in PBMCs of 100 patients with HBV-related HCC, 100 patients with chronic HBV infection and 100 healthy controls. Based on ROC analysis, BHLHE40 and DDIT4 displayed better diagnostic performance than alpha-fetoprotein (AFP) in discriminating HCC from controls. Additionally, BHLHE40 and DDIT4 had high sensitivity for detecting AFP-negative and early-stage HCC. BHLHE40 was also emerged as an independent prognostic factor of overall survival of HCC. Together, our study indicated that BHLHE40 in PBMCs could be a promising diagnostic and prognostic biomarker for HBV-related HCC.

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Circular RNAs: Potential Applications as Therapeutic Targets and Biomarkers in Breast Cancer

Non-Coding RNA ◽

10.3390/ncrna7010002 ◽

2021 ◽

Vol 7 (1) ◽

pp. 2

Author(s):

Debina Sarkar ◽

Sarah D. Diermeier

Keyword(s):

Breast Cancer ◽

Translational Regulation ◽

Closed Loop ◽

Mechanisms Of Action ◽

Circular Rnas ◽

Therapeutic Approaches ◽

Mirna Sponge ◽

Bodily Fluids ◽

Potential Applications ◽

Non Coding Rnas

Circular RNAs (circRNAs) are a class of non-coding RNAs that form a covalently closed loop. A number of functions and mechanisms of action for circRNAs have been reported, including as miRNA sponge, exerting transcriptional and translational regulation, interacting with proteins, and coding for peptides. CircRNA dysregulation has also been implicated in many cancers, such as breast cancer. Their relatively high stability and presence in bodily fluids makes cancer-associated circRNAs promising candidates as a new biomarker. In this review, we summarize the research undertaken on circRNAs associated with breast cancer, discuss circRNAs as biomarkers, and present circRNA-based therapeutic approaches.

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CircTP63 promotes hepatocellular carcinoma progression by sponging miR-155-5p and upregulating ZBTB18

Cancer Cell International ◽

10.1186/s12935-021-01753-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jiantao Wang ◽

Jinbiao Che

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Lines ◽

Circular Rnas ◽

Epithelial Cell Line ◽

High Morbidity ◽

Mrna Levels ◽

Promoting Effect ◽

Tumor Stages ◽

Hcc Cells

Abstract Background Hepatocellular carcinoma (HCC) is the leading cause of tumor-related death worldwide due to high morbidity and mortality, yet lacking effective biomarkers and therapies. Circular RNAs (circRNAs) are a group of non-coding RNAs that regulate gene expression through interacting with miRNAs, implicating in the tumorigenesis and progression. A novel circRNA, circTP63, was reported to be an oncogene in HCC. However, its role in HCC remains unclear. Methods qRT-PCR was used to assess the mRNA levels of CircTP63 in 90 pairs of tumor and adjacent normal tissues from HCC patients, one human normal hepatic epithelial cell line and HCC cell lines. CCK-8, colony formation, transwell, and flow cytometry assays were performed to detect the cellular function of circTP63/miR-155-5p/ZBTB18 in HCC cells. HCC xenograft mice models were established to assess the in vivo effect of circTP63. Bioinformatic analysis, RNA pull-down and luciferase assays were used to determine the interaction among circTP63/miR-155-5p/ZBTB18. Results circTP63 was significantly upregulated in HCC tissues and cell lines. High circTP63 expression is closely associated with the tumor stages, lymph node metastasis, and poor prognosis of HCC patients. Functionally, knockdown of circTP63 inhibited cell proliferation, migration, invasion, and promoted cell apoptosis of HCC. Meanwhile, overexpression of circTP63 enhanced HCC progression. Mechanically, circTP63 was a sponge of miR-155-5p to facilitate the ZBTB18 expression, and the ZBTB18 expression in HCC tissues was negatively associated with the survival rate of HCC patients. Furthermore, rescued assays revealed that the reduced tumor-promoting effect on HCC cells induced by knockdown of circTP63 can be reversed by miR-155-5p inhibitor or ZBTB18 overexpression. Conclusion Our data highlight a critical circTP63-miR-155-5p-ZBTB18 regulatory network involved in the HCC progression, gaining mechanistic insights into the function of circRNAs in HCC progression, and providing effective biomarkers and therapeutic targets for HCC treatment.

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Advances in the Identification of Circular RNAs and Research Into circRNAs in Human Diseases

Frontiers in Genetics ◽

10.3389/fgene.2021.665233 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shihu Jiao ◽

Song Wu ◽

Shan Huang ◽

Mingyang Liu ◽

Bo Gao

Keyword(s):

Neurological Disorders ◽

Closed Loop ◽

Significant Proportion ◽

Human Diseases ◽

Circular Rnas ◽

The Status ◽

Research Questions ◽

Non Coding Rnas ◽

Microrna Sponges

Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs (ncRNAs) with a closed-loop structure that are mainly produced by variable processing of precursor mRNAs (pre-mRNAs). They are widely present in all eukaryotes and are very stable. Currently, circRNA studies have become a hotspot in RNA research. It has been reported that circRNAs constitute a significant proportion of transcript expression, and some are significantly more abundantly expressed than other transcripts. CircRNAs have regulatory roles in gene expression and critical biological functions in the development of organisms, such as acting as microRNA sponges or as endogenous RNAs and biomarkers. As such, they may have useful functions in the diagnosis and treatment of diseases. CircRNAs have been found to play an important role in the development of several diseases, including atherosclerosis, neurological disorders, diabetes, and cancer. In this paper, we review the status of circRNA research, describe circRNA-related databases and the identification of circRNAs, discuss the role of circRNAs in human diseases such as colon cancer, atherosclerosis, and gastric cancer, and identify remaining research questions related to circRNAs.

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CircTP63 promotes hepatocellular carcinoma progression by sponging miR-155-5p and upregulating ZBTB18

10.21203/rs.3.rs-63585/v2 ◽

2020 ◽

Author(s):

Jiantao Wang ◽

Jinbiao Che

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Lines ◽

Circular Rnas ◽

Epithelial Cell Line ◽

High Morbidity ◽

Mrna Levels ◽

Promoting Effect ◽

Tumor Stages ◽

Hcc Cells

Abstract Background: Hepatocellular carcinoma (HCC) is the leading cause of tumor-related death worldwide due to high morbidity and mortality, yet lacking effective biomarkers and therapies. Circular RNAs (circRNAs) are a group of non-coding RNAs that regulate gene expression through interacting with miRNAs, implicating in the tumorigenesis and progression. A novel circRNA, circTP63, was reported to be an oncogene in HCC. However, its role in HCC remains unclear.Methods: qRT-PCR was used to assess the mRNA levels of CircTP63 in 90 pairs of tumor and adjacent normal tissues from HCC patients, one human normal hepatic epithelial cell line and HCC cell lines. CCK-8, colony formation, transwell, and flow cytometry assays were performed to detect the cellular function of circTP63/miR-155-5p/ZBTB18 in HCC cells. HCC xenograft mice models were established to assess the in vivo effect of circTP63. Bioinformatic analysis, RNA pull-down and luciferase assays were used to determine the interaction among circTP63/miR-155-5p/ZBTB18.Results: circTP63 was significantly upregulated in HCC tissues and cell lines. High circTP63 expression is closely associated with the tumor stages, lymph node metastasis, and poor prognosis of HCC patients. Functionally, knockdown of circTP63 inhibited cell proliferation, migration, invasion, and promoted cell apoptosis of HCC. Meanwhile, overexpression of circTP63 enhanced HCC progression. Mechanically, circTP63 was a sponge of miR-155-5p to facilitate the ZBTB18 expression, and the ZBTB18 expression in HCC tissues was negatively associated with the survival rate of HCC patients. Furthermore, rescued assays revealed that the reduced tumor-promoting effect on HCC cells induced by knockdown of circTP63 can be reversed by miR-155-5p inhibitor or ZBTB18 overexpression.Conclusion: Our data highlight a critical circTP63-miR-155-5p-ZBTB18 regulatory network involved in the HCC progression, gaining mechanistic insights into the function of circRNAs in HCC progression, and providing effective biomarkers and therapeutic targets for HCC treatment.

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GPX4 and GPX7 over-expression in human hepatocellular carcinoma tissues

European Journal of Histochemistry ◽

10.4081/ejh.2015.2540 ◽

2015 ◽

Vol 59 (4) ◽

Cited By ~ 14

Author(s):

E. Guerriero ◽

F. Capone ◽

M. Accardo ◽

A. Sorice ◽

M. Costantini ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Biological Function ◽

Early Stage ◽

Common Type ◽

Over Expression ◽

Diagnosis And Prognosis ◽

Glutathione Peroxidases ◽

Qpcr Analysis ◽

Tumor Tissues ◽

Key Factor

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is still one of the most fatal cancers. Hence, it needs to identify always new putative markers to improve its diagnosis and prognosis. The selenium is an essential trace mineral implicated as a key factor in the early stage of cancer and exerts its biological function through the selenoproteins. In the last years our group has been studying the involvement of some selenoproteins in HCC. However, no many data are reported in literature about the correlation between HCC and the glutathione peroxidases (GPXs), both selenium and non selenium-containing GPXs. In this paper we have evaluated the GPX4 and GPX7 expression in some paraffin-embedded tissues from liver biopsy of patients with hepatitis C virus (HCV)-related cirrhosis and HCC by immunohistochemistry and RT-qPCR analysis. Our results evidenced that i) GPX4 and GPX7 had a statistically significant over-expression in HCC tissues compared to cirrhotic counterparts used as non tumor tissues, and ii) their expression was higher in grade III HCC tissues with respect to grade I-II samples. Therefore, we propose to use GPX4 and GPX7 as possible markers for improving HCC diagnosis/prognosis.

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