Hepatoma-derived growth factor promotes liver carcinogenesis by inducing phosphatase and tensin homolog inactivation.

Hepatoma-derived growth factor (HDGF) is located on chromosome 1q21-23, a locus frequently amplified in hepatocellular carcinoma (HCC), and has been proposed as an oncogenic factor by stimulating PI3K/Akt signaling. Phosphatase and tensin homolog (PTEN) acts as a tumor suppressor that antagonizes PI3K/Akt signaling, suggesting a possible regulatory effect of HDGF on PTEN. Here, we aimed to investigate the regulatory role of HDGF on PTEN. The Cancer Genome Atlas (TCGA) cohort study was used to explore molecular significance and outcomes in liver cancer. Resected clinical specimens, consisting of paired tumor and adjacent non-tumor tissue, were analyzed for expressions of HDGF and PTEN in the liver cancer cohort. Liver tissue and primary hepatocytes derived from HDGF knockout mice were analyzed for PTEN status. The influence of HDGF on PTEN was investigated through in vitro and in vivo genetic manipulation studies. The TCGA cohort study revealed an inverse correlation between HDGF and PTEN, with HDGF overexpression emerging as a dominant factor independent of PTEN levels and correlated with poor outcomes in HCC patients. Paired clinical specimens revealed HDGF upregulation in tumor tissue is relevant to elevated α-fetoprotein, and poor survival and recurrent outcomes in liver cancer cohort. HDGF knockout mice exhibited increased liver p-PTEN levels and decreased PTEN expression. Furthermore, in vitro study validated that overexpression of HDGF increased p-PTEN levels and tumor growth, while knockdown of HDGF yielded inverse results. Treatment with recombinant HDGF confirmed the stimulation of p-PTEN and accumulation of PIP₃. Blockade of HDGF and CK2 signaling using anti-HDGF and a CK2 inhibitor validated the stimulation of p-PTEN. Our results reveal that HDGF is an oncogene frequently amplified and upregulated, leading to suppression of PTEN expression and activity, thereby contributing to malignant progression in liver cancer. HDGF upregulation in resected paired-HCC specimens may constitute a valuable prognostic biomarker for HCC patients.