Abstract 5399: Placental gene PEG10 promotes onco-fetal metabolic reprogramming in hepatocellular carcinoma

Abstract Tumorigenesis is a complex biological process, accompanied by cellular dedifferentiation and metabolic reprogramming, which similarities to the metabolic characteristics of embryonic development stages. In our research, we focused particularly on the RNA-binding protein PEG10, which is highly expressed in the placenta and found to be similarly overexpressed in liver cancer cells, playing a key role in the process of aerobic glycolysis in tumor cells. This discovery suggests that there may be a phenomenon of fetal-like metabolic reprogramming in hepatocellular carcinoma (HCC), which is of significant importance for understanding the pathogenesis of HCC and for seeking new therapeutic strategies. In hepatocellular carcinoma (HCC) cells, we found that PEG10 enhances the stability of mRNA for key glycolytic genes hexokinase2 (HK2) and Glucose transporter 1 (GLUT1) by inhibiting the STAU1-mediated RNA degradation pathway, thereby promoting aerobic glycolysis in tumor cells. This process not only promotes the proliferation of tumor cells but also reduces the sensitivity of tumor cells to sorafenib. Furthermore, we observed in clinical samples that high expression of PEG10 is closely associated with poor prognosis in HCC patients, further confirming the important role of PEG10 in the development of HCC. Our research also found that retinoic acid can effectively inhibit aerobic glycolysis in tumor cells by suppressing the transcriptional expression of PEG10, thereby inhibiting the growth of tumor cells. In animal models, mice with liver-specific PEG10 gene knockout showed significant resistance to oncogene-induced liver cancer occurrence and development, providing strong evidence for PEG10 as a therapeutic target. These findings not only reveal the biological link between PEG10 and onco-fetal metabolic reprogramming at the molecular level but also indicate from a clinical perspective that PEG10 may be a potential biomarker and therapeutic target for HCC. The high expression of PEG10 is associated with poor prognosis in HCC patients, and the inhibitory effect of retinoic acid on PEG10 expression provides a new strategy for the treatment of HCC. These results provide new ideas for the future diagnosis and treatment of HCC, especially in the development of targeted therapeutic drugs against PEG10, which has important application prospects. Our research has laid a solid foundation for a deeper understanding of the metabolic reprogramming mechanisms of HCC and the development of new therapeutic methods. Citation Format: Dong Yin, Xinyi Yao, Jingyuan Zhang, Yin Zhang, Jianyou Liao, Kaishun Hu, Jiehua He, Daning Lu. Placental gene PEG10 promotes onco-fetal metabolic reprogramming in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5399.