ArticleSignal transduction and targeted therapy2024
The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma.
Article in Signal transduction and targeted therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed.
- Deubiquitinases as Regulators and Therapeutic Targets in Vascular Diseases.International journal of molecular sciences · 2026Review
- Exosomal circ-ZNF652 Mediates TGF-β1-Induced Epithelial-Mesenchymal Transition and Glycolytic Reprogramming to Promote Hepatocellular Carcinoma Progression.Journal of microbiology and biotechnology · 2026Article
- Hypoxia-inducible factor-1α promotes the malignant progression of cervical cancer cells by regulating lactate dehydrogenase A-mediated glycolysis.Translational cancer research · 2026Article
- SPACE-seq integrates spatial transcriptomics and lineage tracing in native tissues.Cell stem cell · 2026Article
- Article
- Review Article: Biomarkers in Liver Transplantation for Hepatocellular Carcinoma: Towards Precision Medicine.Alimentary pharmacology & therapeutics · 2026Review
- HIFs: The central drivers of tumors and their role as molecular switches in targeted therapy?Acta pharmaceutica Sinica. B · 2026Review
- FLRT2 promotes foam cell formation and atherosclerosis by inhibiting USP22-mediated ABCA1 deubiquitination.Acta pharmacologica Sinica · 2026Article
- Remodelling the tumour microenvironment and beyond: ERO1A as a multifaceted regulator and emerging therapeutic target in cancer.Clinical and translational medicine · 2026Review
- Self-Assembly of Stimuli-Responsive Peptide Enhances Therapeutics by Specifically Disrupting Hepatocellular Carcinoma Lysosomes In Vivo.Advanced materials (Deerfield Beach, Fla.) · 2026Article
- Calcium peroxide loaded liposomes reprogram hypoxic and acidic tumor microenvironment to overcome lenvatinib resistance in hepatocellular carcinoma.Materials today. Bio · 2026Article
- Understanding how hypoxia contributes to liver cancer stem cells maintenance.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Activation of methionine metabolism mediated by HNF4α confers ferroptosis resistance in hepatocellular carcinoma.Cell death discovery · 2026Article
- The role of e3 ubiquitin ligases and deubiquitinating enzymes in hepatocellular carcinoma.Cell biology and toxicology · 2026Review
- Protein expression profiling of lenvatinib-resistant liver cancer cells and identify B4GALT4 as a critical drug resistance molecule.Discover oncology · 2026Article
- LAMTOR5 promotes hepatoma growth in mice by disrupting LC3-p62-mediated autophagy and preventing p62 proteasome degradation.Acta pharmacologica Sinica · 2026Article
- Targeting KIF23 inhibits cell proliferation and primary chemoresistance in cervical cancer by inactivating the MYH9/MCM2/PCNA pathway.Clinical and translational medicine · 2026Article
- HIF1α Attenuated the Lung Ischemia-Reperfusion Injury by Activating the miR-485/Notch1 Signalling.Journal of cellular and molecular medicine · 2026Article
- The central regulator HIF-1α in digestive system pathologies: inflammation and cancer.Frontiers in immunology · 2026Review
- Targeting ubiquitin-specific peptidase 22 in solid tumours: from ubiquitination to immunotherapy.Frontiers in cell and developmental biology · 2026Review
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Authors and funding
23 authors.
Funding
Abstract
Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance. We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α (HIF-1α) pathway activation is responsible for acquired LR in HCC. Phosphorylated non-muscle myosin heavy chain 9 (MYH9) at Ser1943, p-MYH9 (Ser1943), could recruit ubiquitin-specific protease 22 (USP22) to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC. Clinically, p-MYH9 (Ser1943) expression was upregulated in HCC samples, which predicted poor prognosis and LR. A casein kinase-2 (CK2) inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro. Therefore, the p-MYH9 (Ser1943)/USP22/HIF-1α axis is critical for LR and cancer stemness. For the diagnosis and treatment of LR in HCC, p-MYH9 (Ser1943), USP22, and HIF-1α might be valuable as novel biomarkers and targets.
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