ArticleCell death discovery2025
N6-methyladenosine-modification of USP15 regulates chemotherapy resistance by inhibiting LGALS3 ubiquitin-mediated degradation via AKT/mTOR signaling activation pathway in hepatocellular carcinoma.
Article in Cell death discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Ubiquitin Specific Peptidase 48 Deubiquitinates METTL3 to Modulate Ferroptosis in Gastric Cancer Cells.Molecular carcinogenesis · 2026Article
- Injectable multi-component hydrogel as an inhibitor of choline kinase α achieved the treatment of malignant ascites by inhibiting PI3K/AKT/mTOR signaling pathway.Journal of advanced research · 2026Article
- Near-infrared/glutathione-activated CRISPR/Cas13a sensing platform for the detection of multiple microRNAs.RSC advances · 2026Article
- Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review).International journal of oncology · 2026Review
- Expression, Localization and Actions of Galectin-3: Implications in the Pathophysiology and Therapy of Cardiovascular Disease.International journal of molecular sciences · 2026Review
- Post-translational modification in hepatocellular carcinoma resistance: molecular mechanisms and therapeutic targeting.Frontiers in immunology · 2026Review
- Melatonin-engineered MSCs-exosomes deliver USP4 to stabilise ARNTL and inhibit clock rhythmic ferroptosis for enhanced flap survival.Clinical and translational medicine · 2026Article
- Recent advances in m6A RNA modification in hepatocellular carcinoma: from mechanisms to therapeutic potential.Frontiers in molecular biosciences · 2026Review
- [Knockdown ofNan fang yi ke da xue xue bao = Journal of Southern Medical University · 2025Article
- Resistance of first-line targeted drugs in hepatocellular carcinoma: the epigenetic regulation mechanisms.Cell death & disease · 2025Review
- Targeting RNA adenosine editing and modification enzymes for RNA therapeutics.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
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Authors and funding
9 authors.
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Abstract
Hepatocellular carcinoma (HCC) is among the most malignant tumors and seriously threatens human health worldwide, and its incidence rate is increasing annually. USP15 is a member of the ubiquitination-specific protease (USP) family, which can regulate protein ubiquitination, thereby affecting their stability, and is dysregulated in many cancers, but its expression and regulatory mechanism in HCC are unclear. The aims of this study were to explore the role and mechanism of USP15 in regulating HCC cell stemness, proliferation, and lenvatinib resistance. Immunohistochemistry and high-throughput sequencing analyses of tumor and adjacent normal tissue samples from 52 patients with HCC were conducted. Functional analyses of immortalized human liver and HCC cell lines were conducted, including quantitative real-time PCR; western blot; plasmid, lentivirus, and siRNA transfection; co-immunoprecipitation; mass spectrometry; MeRIP-qPCR; and ubiquitination, cell growth, colony formation, and spheroid formation assays. HCC tumor growth was also assessed using cell transplantation in nude mice. We found that USP15 is upregulated in HCC and affects patient prognosis. Our results demonstrated that USP15 can increase LGALS3 stability in HCC through deubiquitination modification, and affect the stemness, proliferation, and lenvatinib resistance of HCC cells by activating the AKT/mTOR pathway. USP15 expression levels were positively correlated with HCC cell stemness, proliferation, and lenvatinib resistance. In addition, methyltransferase-like protein 3 (Mettl3) N6-methyladenosine (m6A) modified USP15 to upregulate its levels by increasing its mRNA stability. These findings provide a theoretical basis for the potential discovery of new HCC oncogenes, as well as the identification of effective targets and development of novel anti-HCC drugs and clinical applications.
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Registered trials
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