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      The Maturation of Tumor Suppressor miR-497 in Hepatocellular Carcinoma is Inhibited by Oncogenic circRNA SCARB1

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          Abstract

          Introduction

          Circular RNA (CircRNA) SCARB1 plays an oncogenic role in renal cell carcinoma, while its role in other cancers is unclear. The aim of this study was to explore the role of circRNA SCARB1 in hepatocellular carcinoma (HCC).

          Methods

          The expression of circRNA SCARB1, mature miR-497 and miR-497 precursor in HCC and paired non-tumor tissues from 64 HCC patients were analyzed by RT-qPCR. CircRNA SCARB1 was overexpressed in HCC cells, followed by the measurement of the expression levels of both mature miR-497 and miR-497 precursor to evaluate the effects of overexpression of circRNA SCARB1 on the maturation of miR-497. The effects of circRNA SCARB1 and miR-497 on the proliferation and migration of HCC cells were assessed by CCK-8 assay and Transwell assay, respectively.

          Results

          We found that circRNA SCARB1 was upregulated in HCC. In addition, mature miR-497 and miR-497 were downregulated in HCC. Correlation analysis showed that circRNA SCARB1 was inversely correlated with mature miR-497 but not miR-497 precursor. Consistently, in HCC cells, downregulated mature miR-497, but not miR-497 precursor, was observed in HCC cells transfected with circRNA SCARB1 expression vector. Analysis of cellular behaviors showed that overexpression of circRNA SCARB1 increased the proliferation and migration of HCC cells, while overexpression of miR-497 decreased cell proliferation and migration. Moreover, overexpression of miR-497 reduced the effects of overexpression of circRNA SCARB1.

          Discussion

          Therefore, circRNA SCARB1 is upregulated in HCC and promotes HCC cell proliferation and migration by suppressing the maturation of miR-497.

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          Most cited references19

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          Natural RNA circles function as efficient microRNA sponges.

          MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.
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            CircRNA: functions and properties of a novel potential biomarker for cancer

            Circular RNAs, a novel class of endogenous noncoding RNAs, are characterized by their covalently closed loop structures without a 5′ cap or a 3′ Poly A tail. Although the mechanisms of circular RNAs’ generation and function are not fully clear, recent research has shown that circular RNAs may function as potential molecular markers for disease diagnosis and treatment and play an important role in the initiation and progression of human diseases, especially in tumours. This review summarizes some information about categories, biogenesis, functions at the molecular level, properties of circular RNAs and the possibility of circular RNAs as biomarkers in cancers.
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              Epidemiology of viral hepatitis and hepatocellular carcinoma.

              Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Cancer Manag Res
                Cancer Manag Res
                cmar
                cancmanres
                Cancer Management and Research
                Dove
                1179-1322
                16 July 2021
                2021
                : 13
                : 5751-5759
                Affiliations
                [1 ]Department of Hepatobiliary Surgery, Xuzhou Cancer Hospital , Xuzhou City, Jiangsu Province, 221000, People’s Republic of China
                [2 ]Department of Clinical Laboratory, Xuzhou Cancer Hospital , Xuzhou City, Jiangsu Province, 221000, People’s Republic of China
                Author notes
                Correspondence: Yiren Ding Department of Hepatobiliary Surgery, Xuzhou Cancer Hospital , No. 131 Huancheng Road, Gulou District, Xuzhou City, Jiangsu Province, 221000, People’s Republic of China Email yirendingxuzhou@163.com
                Article
                304125
                10.2147/CMAR.S304125
                8292958
                3c16b624-77f0-4c4b-9006-16b71626cea3
                © 2021 Zhu et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 31 January 2021
                : 11 June 2021
                Page count
                Figures: 5, Tables: 1, References: 19, Pages: 9
                Funding
                Funded by: No funding;
                No funding was received.
                Categories
                Original Research

                Oncology & Radiotherapy
                hepatocellular carcinoma,circrna scarb1,mir-497,precursor,maturation
                Oncology & Radiotherapy
                hepatocellular carcinoma, circrna scarb1, mir-497, precursor, maturation

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