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      Elevated levels of hsa_circ_006100 in gastric cancer promote cell growth and metastasis via miR‐195/GPRC5A signalling

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          Abstract

          Objectives

          Circular RNAs (circRNAs) are non‐coding RNAs, some of which are thought to be involved in gastric cancer development. Here, we examined the functions of circRNA hsa_circ_006100 in gastric cancer cells and an animal model of gastric cancer.

          Materials and Methods

          The expression of hsa_circ_006100, miR‐195 and various functional genes was determined by quantitative RT‐PCR. Cell viability, clone formation, apoptosis and cell migration/invasion abilities were analysed by the CCK‐8 assay, crystal violet staining, Hoechst staining and Transwell assay, respectively. A tumour model was established by subcutaneously injecting tumour cells into nude mice. Levels of protein expression were analysed by Western blotting and immunohistochemistry.

          Results

          A bioinformatics analysis showed that miR‐195 was negatively co‐expressed with hsa_circ_006100. Patients with a high hsa_circ_006100 level or low miR‐195 level had tumours with a high TNM stage, poor cellular differentiation and lymph node metastasis. miR‐195 was targeted and inhibited by hsa_circ_006100. Overexpression of hsa_circ_006100 enhanced cellular viability and proliferation, while miR‐195 suppressed hsa_circ_006100‐enhanced cell growth and induced apoptosis in MGC‐803 and AGS cells. Forced hsa_circ_006100 expression promoted the migration and invasion of MGC‐803 and AGS cells, while those activities were inhibited by miR‐195. Mechanistically, GPRC5A was predicted as a target of miR‐195 and was upregulated in gastric cancer. A miR‐195 inhibitor restored cell viability, proliferation, migration and invasion, and repressed apoptosis via GPRC5A. In vivo studies showed that knockdown of hsa_circ_006100 delayed tumour growth, reduced PCNA expression and upregulated miR‐195 and BCL‐2 expression which was restored by miR‐195 inhibition due to GPRC5A/EGFR signalling, and changed the EMT phenotype in vivo.

          Conclusions

          Hsa_circ_006100 functions as an oncogene in gastric cancer and exerts its effects via miR‐195/GPRC5A signalling.

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          Most cited references9

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          Recent patterns in gastric cancer: a global overview.

          Paola Bertuccio, Liliane Chatenoud, Fabio Levi … (2009)
          Until the mid-1990s, gastric cancer has been the first cause of cancer death worldwide, although rates had been declining for several decades and gastric cancer has become a relatively rare cancer in North America and in most Northern and Western Europe, but not in Eastern Europe, Russia and selected areas of Central and South America or East Asia. We analyzed gastric cancer mortality in Europe and other areas of the world from 1980 to 2005 using joinpoint regression analysis, and provided updated site-specific incidence rates from 51 selected registries. Over the last decade, the annual percent change (APC) in mortality rate was around -3, -4% for the major European countries. The APC were similar for the Republic of Korea (APC = -4.3%), Australia (-3.7%), the USA (-3.6%), Japan (-3.5%), Ukraine (-3%) and the Russian Federation (-2.8%). In Latin America, the decline was less marked, but constant with APC around -1.6% in Chile and Brazil, -2.3% in Argentina and Mexico and -2.6% in Colombia. Cancers in the fundus and pylorus are more common in high incidence and mortality areas and have been declining more than cardia gastric cancer. Steady downward trends persist in gastric cancer mortality worldwide even in middle aged population, and hence further appreciable declines are likely in the near future.
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            Gastric cancer: prevention, screening and early diagnosis.

            Victor Pasechnikov, Sergej Chukov, Evgeny Fedorov … (2014)
            Gastric cancer continues to be an important healthcare problem from a global perspective. Most of the cases in the Western world are diagnosed at late stages when the treatment is largely ineffective. Helicobacter pylori (H. pylori) infection is a well-established carcinogen for gastric cancer. While lifestyle factors are important, the efficacy of interventions in their modification, as in the use of antioxidant supplements, is unconvincing. No organized screening programs can be found outside Asia (Japan and South Korea). Although several screening approaches have been proposed, including indirect atrophy detection by measuring pepsinogen in the circulation, none of them have so far been implemented, and more study data is required to justify any implementation. Mass eradication of H. pylori in high-risk areas tends to be cost-effective, but its adverse effects and resistance remain a concern. Searches for new screening biomarkers, including microRNA and cancer-autoantibody panels, as well as detection of volatile organic compounds in the breath, are in progress. Endoscopy with a proper biopsy follow-up remains the standard for early detection of cancer and related premalignant lesions. At the same time, new advanced high-resolution endoscopic technologies are showing promising results with respect to diagnosing mucosal lesions visually and targeting each biopsy. New histological risk stratifications (classifications), including OLGA and OLGIM, have recently been developed. This review addresses the current means for gastric cancer primary and secondary prevention, the available and emerging methods for screening, and new developments in endoscopic detection of early lesions of the stomach.
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              Circular RNA has_circ_0067934 is upregulated in esophageal squamous cell carcinoma and promoted proliferation

              Wenjia Xia, Mantang Qiu, Rui-rui Chen … (2016)
              Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent and deadly types of cancer worldwide especially in Eastern Asia and the prognosis of ESCC remain poor. Recent evidence suggests that circular RNAs (circRNAs) play important roles in multiple diseases, including cancer. In this study, we characterized a novel circRNA termed hsa_circ_0067934 in ESCC tumor tissues and cell lines. We analyzed a cohort of 51 patients and found that hsa_circ_0067934 was significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues. The high expression level of hsa_circ_0067934 was associated with poor differentiation (P = 0.025), I-II T stage (P = 0.04), and I-II TNM stage (P = 0.021). The in vitro silence of hsa_circ_0067934 by siRNA inhibited the proliferation and migration of ESCC cells and blocked cell cycle progression. Cell fraction analyses and fluorescence in situ hybridization detected that hsa_circ_0067934 was mostly located in the cytoplasm. Our findings suggest that hsa_circ_0067934 is upregulated in ESCC tumor tissue. Our data suggest that hsa_circ_0067934 represents a novel potential biomarker and therapeutic target of ESCC.
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                Author and article information

                Contributors
                Xinke Zhou: zxkstarr@yeah.com
                Yanfang Zheng:
                ORCID: https://orcid.org/0000-0002-5591-6425
                18665000236@163.com
                Journal
                Journal ID (nlm-ta): Cell Prolif
                Journal ID (iso-abbrev): Cell Prolif
                Journal ID (doi): 10.1111/(ISSN)1365-2184
                Journal ID (publisher-id): CPR
                Title: Cell Proliferation
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0960-7722
                ISSN (Electronic): 1365-2184
                Publication date (Electronic): 18 July 2019
                Publication date Collection: September 2019
                Volume: 52
                Issue: 5 ( doiID: 10.1111/cpr.v52.5 )
                Electronic Location Identifier: e12661
                Affiliations
                [ 1 ] Department of Oncology Zhujiang Hospital of Southern Medical University Guangzhou China
                [ 2 ] Department of Oncology the Fifth Affiliated Hospital of Guangzhou Medical University Guangzhou China
                [ 3 ] Department of General Surgery The Fifth Affiliated Hospital of Guangzhou Medical University Guangzhou China
                [ 4 ] Department of Center Laboratory The Fifth Affiliated Hospital of Guangzhou Medical University Guangzhou China
                Author notes
                [*] [* ] Correspondence

                Yanfang Zheng, Department of Oncology, Zhujiang Hospital of Southern Medical University, No. 253 Industry Road, Guangzhou 510282, China.

                Email: 18665000236@ 123456163.com

                Xinke Zhou, Department of oncology, the Fifth Affiliated Hospital of Guangzhou Medical University, 621 Harbor Road, Guangzhou 510700, China.

                Email: zxkstarr@ 123456yeah.com

                Author information
                https://orcid.org/0000-0002-5591-6425
                Article
                Publisher ID: CPR12661
                DOI: 10.1111/cpr.12661
                PMC ID: 6797516
                PubMed ID: 31318114
                SO-VID: fba75d8b-579b-4451-a971-5b0e29a673a4
                Copyright © © 2019 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 12 December 2018
                Date revision received : 14 April 2019
                Date accepted : 19 June 2019
                Page count
                Figures: 6, Tables: 3, Pages: 11, Words: 6134
                Funding
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81673206
                Funded by: Science and Technology Projects of Guangzhou City
                Award ID: 201508020262
                Award ID: C2016060
                Funded by: Medical Scientific Research Foundation of Guangdong Province of China
                Categories
                Subject: Original Article
                Subject: Original Articles
                Custom metadata
                source-schema-version-number 2.0
                cover-date September 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:05.12.2019

                ScienceOpen disciplines: Cell biology
                Keywords: circrna,gastric cancer,gprc5a,mir‐195
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: circrna, gastric cancer, gprc5a, mir‐195

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