RESUMO
Hepatocellular carcinoma (HCC) is an aggressive malignancy without effective therapeutic approaches. Here, we evaluate the tumor-intrinsic mechanisms that attenuate the efficacy of immune checkpoint inhibitor (ICI) that is observed in patients with advanced HCC who progress on first-line tyrosine kinase inhibitor (TKI) therapy. Upregulation of AXL observed in sorafenib- and lenvatinib-resistant HCCs is correlated with poor response towards TKI and ICI treatments. AXL upregulation protects sorafenib-resistant HCC cells from oxidative stress, mitochondrial damage, and accompanying immunogenic cell death through suppressed tumor necrosis factor-α (TNF-α) and STING-type I interferon pathways. Pharmacological inhibition of AXL abrogates the protective effect and re-sensitizes TKI-resistant HCC tumors to anti-PD-1 treatment. We suggest that targeting AXL in combination with anti-PD-1 may provide an alternative treatment scheme for HCC patients who progress on TKI treatment.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death. The accumulation of genetic and epigenetic changes is closely related to the occurrence and development of HCC. Enhancer of zeste homolog 2 (EZH2, a histone methyltransferase) is suggested to be one of the principal factors that mediates oncogenesis by acting as a driver of epigenetic alternation. Recent studies show that EZH2 is widely involved in proliferation and metastasis of HCC cells. In this review, the functions of EZH2 in HCC progression, the role of EZH2 in tumor immunity and the application of EZH2-related inhibitors in HCC therapy are summarized.
RESUMO
YAP1 (Yes-associated protein 1) is one of the principal factors that mediates oncogenesis by acting as a driver of gene expression. It has been confirmed to play an important role in organ volume control, stem cell function, tissue regeneration, tumorigenesis and tumor metastasis. Recent research findings show that YAP1 is correlated with the stemness of liver cancer stem cells, and liver cancer stem cells are closely associated with YAP1-induced tumor initiation and progression. This article reviews the advancements made in research on the mechanisms by which YAP1 promotes liver cancer stem cells and discusses some potential mechanisms that require further study.