Abstract
Abstract
Tumors display marked similarities with embryos, exploiting embryonic developmental programs. Beyond the embryo, the placenta also shares features with malignant tumors, such as invasion, immune evasion, and rapid nutrient exchange, highlighting the need for mechanistic investigations of tumor development through the lens of placental biology. In this study, by screening placental-specific genes with aberrant expression in hepatocellular carcinoma (HCC), we found that the paternally expressed gene 10 (PEG10, a retrovirus-like gene) was overexpressed in HCC and associated with poor patient prognosis. Liver-specific deletion of Peg10 significantly impeded hepatocarcinogenesis and tumor progression in a hydrodynamic tail vein injection-induced HCC mouse model. PEG10 drove tumor cells to co-opt the metabolic phenotype of trophoblast cells by upregulating key glucose metabolic regulators glucose transporter 1 (GLUT1) and hexokinase 2 (HK2). Mechanistically, as an RNA-binding protein (RBP), PEG10 inhibited the Staufen1-mediated mRNA decay (SMD) pathway, stabilizing GLUT1 and HK2 mRNA to enhance glucose uptake and aerobic glycolysis. Furthermore, retinoic acid pharmacologically suppressed PEG10 expression, effectively abrogating the adaptive metabolic advantage and acting synergistically with sorafenib to restrict tumor growth. Collectively, this study reveals how HCC aberrantly reactivates the placental gene PEG10 to orchestrate oncogenic glucose uptake and metabolism, identifying it as a compelling therapeutic target for metabolic intervention in cancer.