MARK2 drives the development and progression of hepatocellular carcinoma

MARK2 plays a crucial role in cancer. Therefore, we investigated the effects of MARK2 on stemness regulation in hepatocellular carcinoma (HCC). Samples from HCC patients were collected to examine MARK2 expression and its correlation with CSC characteristics and patients’ prognosis. HCC cells and derived cancer stem cells (CSCs) overexpressing or knocking out MARK2/NR2F2 were established, and Wnt or PI3K/AKT agonists and antagonists were used in combination. The CSC characteristics were evaluated, and the sensitivity to lenvatinib and sorafenib was assessed in an orthotopic tumor model. A primary HCC mouse model was induced, and gene intervention was performed using hepatocyte-targeting AAVs. MARK2 was upregulated in tumor tissues, and its high expression was correlated with an increase in CSC enrichment in tumor tissues and poor outcomes in HCC patients. MARK2 knockout repressed the stem cell-like characteristics of CSCs and their resistance to lenvatinib/sorafenib, which was weakened by Wnt or PI3K/AKT agonists. Overexpression of MARK2 enhanced the stem cell characteristics of HCC cells and resistance to lenvatinib and sorafenib, The combined use of ​Wnt or PI3K/AKT antagonists influenced MARK2’s regulation of HCC stem cell-like characteristics. NR2F2 bound to the MARK2 promoter and activated its transcription, thereby promoting Wnt and PI3K/AKT signaling. NR2F2/MARK2 signaling elevated resistance to lenvatinib and sorafenib in orthotopic tumors and promoted the development of primary HCC. NR2F2 enhances the stem cell-like characteristics of HCC and resistance to lenvatinib and sorafenib by promoting the transcription of MARK2 and activating the Wnt and PI3K/AKT signaling pathways, thereby influencing the development and progression of HCC. Not applicable.