{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T23:51:18Z","timestamp":1767829878012,"version":"3.49.0"},"reference-count":68,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/CBRG\/0095\/2015"],"award-info":[{"award-number":["NMRC\/CBRG\/0095\/2015"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Here, we present a novel strategy to identify key circRNA signatures of clinically relevant co-expressed circRNA-mRNA networks in pertinent cancer-pathways that modulate prognosis of HCC patients, by integrating clinic-pathological features, circRNA and mRNA expression profiles. Through further integration with miRNA expression profiles, clinically relevant competing-endogenous-RNA (ceRNA) networks of circRNA-miRNA-mRNAs were constructed. At least five clinically relevant nodal-circRNAs, co-expressed with numerous genes, were identified from the circRNA-mRNA networks. These nodal circRNAs upregulated proliferation (except circRaly) and transformation in cells. The most upregulated nodal-circRNA, circGPC3, associated with higher-grade tumors and co-expressed with 33 genes, competes with 11 mRNAs for two shared miRNAs. circGPC3 was experimentally demonstrated to upregulate cell-cycle and migration\/invasion in both transformed and non-transformed liver cell-lines. circGPC3 was further shown to act as a sponge of miR-378a-3p to regulate APSM (Abnormal spindle-like microcephaly associated) expression and modulate cell transformation. This study identifies 5 key nodal master circRNAs in a clinically relevant circRNA-centric network that are significantly associated with poorer prognosis of HCC patients and promotes tumorigenesis in cell-lines. The identification and characterization of these key circRNAs in clinically relevant circRNA-mRNA and ceRNA networks may facilitate the design of novel strategies targeting these important regulators for better HCC prognosis.<\/jats:p>","DOI":"10.3390\/cancers13112772","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T10:38:39Z","timestamp":1622630319000},"page":"2772","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Clinicopathological-Associated Regulatory Network of Deregulated circRNAs in Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"13","author":[{"given":"Jian","family":"Han","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Thurnherr","sequence":"additional","affiliation":[{"name":"NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander Y. F.","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Hepato-Pancreato-Biliary & Transplant Surgery, Singapore General Hospital, Singapore 169608, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8218-4576","authenticated-orcid":false,"given":"Brian K. P.","family":"Goh","sequence":"additional","affiliation":[{"name":"Department of Hepato-Pancreato-Biliary & Transplant Surgery, Singapore General Hospital, Singapore 169608, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierce K. H.","family":"Chow","sequence":"additional","affiliation":[{"name":"Department of Hepato-Pancreato-Biliary & Transplant Surgery, Singapore General Hospital, Singapore 169608, Singapore"},{"name":"Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School Singapore, Singapore 169547, Singapore"},{"name":"Department of Surgical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung Yip","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Hepato-Pancreato-Biliary & Transplant Surgery, Singapore General Hospital, Singapore 169608, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng Chung","family":"Cheow","sequence":"additional","affiliation":[{"name":"Department of Hepato-Pancreato-Biliary & Transplant Surgery, Singapore General Hospital, Singapore 169608, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ser Yee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Hepato-Pancreato-Biliary & Transplant Surgery, Singapore General Hospital, Singapore 169608, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tony K. H.","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Pathology, Singapore General Hospital, Singapore 169608, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel S.","family":"Chong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6777-8464","authenticated-orcid":false,"given":"London L. P. J.","family":"Ooi","sequence":"additional","affiliation":[{"name":"Department of Hepato-Pancreato-Biliary & Transplant Surgery, Singapore General Hospital, Singapore 169608, Singapore"},{"name":"Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School Singapore, Singapore 169547, Singapore"},{"name":"Department of Surgical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4323-3635","authenticated-orcid":false,"given":"Caroline G.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore"},{"name":"NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore"},{"name":"Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School Singapore, Singapore 169547, Singapore"},{"name":"Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Level 6, Lab 5, 11 Hospital Drive, Singapore 169610, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.jhep.2006.05.013","article-title":"The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide","volume":"45","author":"Perz","year":"2006","journal-title":"J. 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