Neuro-oncological ventral antigen 1 regulates liver cancer stem cell properties and Lenvatinib resistance via targeting SOX4

Cancer stem cells (CSCs) are essentially linked with the pathogenesis of human cancers. It has been reported that RNA binding protein modulates the stemness of CSCs. This investigation identified that in CSCs, NOVA1 is upregulated. Knockdown of NOVA1 inhibits tumorigenesis and self-renew ability of liver CSCs, whereas its forced expression has opposite effects. The mechanistic analysis revealed that in liver CSCs, SOX4 is a direct NOVA1 target. It enhances tumorigenesis and self-renew ability of liver CSCs by increasing SOX4 mRNA stability by combing with the 3-'UTR. Furthermore, NOVA1 overexpression desensitizes hepatocellular carcinoma (HCC) cells to Lenvatinib-mediated cell development suppression and apoptosis. Patients' cohort analysis indicated that low NOVA1 might predict the benefits of Lenvatinib in HCC individuals. Moreover, knocking down SOX4 could reverse the NOVA1 overexpression-mediated desensitization of HCC cells to Lenvatinib-induced cell apoptosis. In summary, this investigation indicates the essential role of NOVA1 self-renew of CSCs and tumorigenesis in the liver, suggesting it as an optimal HCC therapeutic target.