Targeting of WEE1 suppresses tumorigenecity and cancer stem cell-like phenotype in hepatocellular carcinoma

The current standard-of-care for advanced liver cancer is limited. Therefore, there is an urgent need for development of novel molecular targeted therapy. Increase of WEE1 kinase activity through an epigenetic regulation plays an important role in the development of hepatocellular carcinoma (HCC). Here we demonstrated that WEE1 siRNA silencing caused inhibition of HCC cell growth through blockade of cell cycle progression and induction of apoptosis. The anti-proliferative effects were driven by a subset of molecular alterations including the upregulation of cdk inhibitor p21 and the downregulation of AKT1, CDK2, cyclin B1 (CCNB1), PARP1 and GPAM which are functionally involved in control of cell cycle, apoptosis and lipid metabolism. Systemic delivery of a modified WEE1 siRNA encapsulated in lipid nanoparticles significantly inhibited human HCC growth in murine xenograft models, and increased mice survival. Wee1 silencing in tumor cells also resulted in a strong inhibition of lipogenesis (SREBP1C, FAS) and caused a marked decrease in fat accumulation. Of importance, knockdown of WEE1 dramatically reduced the portion of liver cancer stem cells (CSCs) population through co-downregulation of cancer stemness genes and weakened the capacity of sphere formation and the ability of cancer cell migration. Our findings suggest that the epigenetic modifier WEE1 functionally involve to HCC lipid metabolism and CSC-like phenotype maintenance and that molecular targeting of WEE1 may be an effective systemic therapy for prevention of tumor recurrence via elimination of CSCs in liver tumor microenvironment.

8