Oncofetal MCB1 Is a Functional Biomarker for HCC Personalized Therapy

Abstract Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related death worldwide and lacks biomarkers for personalized therapy. Herein, it is reported that MCB1 could be a novel oncofetal protein that is upregulated in the preneoplastic lesions and serum of early HCC patients. Functional studies reveal that MCB1 modulated p53 protein degradation to promote T‐IC generation and drive HCC initiation. Furthermore, the MCB1/p53 axis is shown to determine the responses of hepatoma cells to conventional chemotherapeutics and predict transcatheter arterial chemoembolization (TACE) benefits in patients. Importantly, MCB1 can mediate sorafenib/lenvatinib resistance by downregulating two essential drug targets fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 3 (VEGFR3) expression in a proteasome‐dependent manner. Patient‐derived tumor organoids (PDOs), patient‐derived xenografts (PDXs), and patient cohorts analysis suggested that MCB1 levels in HCCs may determine the distinct responses to conventional therapeutics and targeted drugs. Furthermore, treatment of targeted drugs‐resistant HCC with adeno‐associated virus (AAV) targeting MCB1 or a proteasome inhibitor restores targeted drug response, suggesting their clinical significance in HCC combinational therapy. In conclusion, these findings demonstrate that MCB1 could act as a driver for HCC initiation, a contributor to drug resistance, and a biomarker for individualized HCC therapy.