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miR-199a-5p/GPR89A axis modulates sorafenib resistance in hepatocellular carcinoma through glutamate metabolic reprogramming.
Article in Science progress. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- A malignant symbiosis: The neuro-metabolic symphony rewires the tumor microenvironment.Neoplasia (New York, N.Y.) · 2026Review
- Pathological Complete Response in Advanced Hepatocellular Carcinoma With Portal Vein Tumor Thrombus Following Conversion Therapy With TACE, HAIC, Lenvatinib, and Sintilimab: A Case Report.Clinical case reports · 2026Article
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ObjectiveSorafenib 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.MethodsTo generate sorafenib-resistant HCC cell lines, cells were cultured in medium with 10 μM sorafenib. GPR89A expression in these cells was examined by quantitative reverse transcription-polymerase 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.ResultsWe 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.ConclusionsThese findings uncover a novel regulatory axis linking GPR89A overexpression, glutamate metabolic reprogramming, and the development of acquired sorafenib-resistant HCC.
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