{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T06:22:08Z","timestamp":1780986128181,"version":"3.54.1"},"reference-count":53,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Foundation for fostering the Peiyuan Research Project of The Affiliated Hospital of Hangzhou Normal University","award":["PYJH202403"],"award-info":[{"award-number":["PYJH202403"]}]},{"name":"Natural Science Research Project of Anhui Educational Committee","award":["2022AH051450"],"award-info":[{"award-number":["2022AH051450"]}]},{"name":"Open Project of Anhui Provincial Key Laboratory","award":["MBZZ202404"],"award-info":[{"award-number":["MBZZ202404"]}]},{"name":"Anhui Province Top and Young Talents Project","award":["gxyq2022044"],"award-info":[{"award-number":["gxyq2022044"]}]},{"DOI":"10.13039\/501100003995","name":"Natural Science Foundation of Anhui Province","doi-asserted-by":"publisher","award":["2208085MH247"],"award-info":[{"award-number":["2208085MH247"]}],"id":[{"id":"10.13039\/501100003995","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Science Progress"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Sorafenib is a key targeted therapeutic agent for hepatocellular carcinoma (HCC). However, the emergence of drug resistance greatly limits its clinical efficacy. We found that GPR89A is markedly overexpressed in both sorafenib-resistant HCC cell lines and clinical tumor specimens. Nevertheless, the exact biological role of GPR89A in sorafenib-resistant HCC remains to be elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To generate sorafenib-resistant HCC cell lines, cells were cultured in medium with 10 \u03bcM sorafenib. GPR89A expression in these cells was examined by quantitative reverse transcription\u2013polymerase chain reaction and Western blot. The impact of GPR89A inhibition on cell proliferation was assessed using cell counting kit-8 and colony formation assays. Bioinformatics predicted miR-199a-5p binding sites in the GPR89A promoter region; luciferase reporter assays were conducted with wild-type or mutant promoter sequences. Glutamate in culture supernatants was measured by enzyme-linked immunosorbent assay, and exogenous glutamate showed dose-dependent inhibition of resistant cell proliferation (MTT assay). Clinical correlation analysis involved 30 pairs of advanced HCC samples. Pearson analysis revealed significant inverse correlations among miR-199a-5p, GPR89A, and metabotropic glutamate receptor 1 (mGluR1) expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that the cell surface transmembrane protein GPR89A was substantially overexpressed in both sorafenib-resistant HCC cell lines and clinical tumor specimens. Importantly, higher GPR89A expression levels were positively correlated with an increased degree of sorafenib resistance in clinical samples. In sorafenib-resistant HCC tissues, the expression of both GPR89A and mGluR1 was significantly upregulated, whereas miR-199a-5p levels were markedly reduced. Correlation analysis revealed a negative association between GPR89A and miR-199a-5p expression, and a positive association between GPR89A and mGluR1. Mechanistically, miR-199a-5p directly targets GPR89A mRNA to suppress its expression, thereby downregulating mGluR1 and reducing glutamate levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings uncover a novel regulatory axis linking GPR89A overexpression, glutamate metabolic reprogramming, and the development of acquired sorafenib-resistant HCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/00368504251381592","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T04:58:59Z","timestamp":1758603539000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["miR-199a-5p\/GPR89A axis modulates sorafenib resistance in hepatocellular carcinoma through glutamate metabolic reprogramming"],"prefix":"10.1177","volume":"108","author":[{"given":"Yao","family":"Li","sequence":"first","affiliation":[{"name":"Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Anhui Provincial Key Laboratory of Infection and Immunology, and Department of Laboratory Medicine, Bengbu Medical University, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, School of Medicine, Beihua University, Jilin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangliang","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulin","family":"Du","sequence":"additional","affiliation":[{"name":"Anhui Provincial Key Laboratory of Immunology in Chronic 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