UPF1 Impacts on mTOR Signaling Pathway and Autophagy in Endometrioid Endometrial Carcinoma

Abstract

Endometrioid endometrial carcinoma (EEC) is one of the most common malignant gynecologic tumors worldwide. Most EEC cases are associated with activities of the mTOR pathway, which regulates protein synthesis, cell growth and autophagy. While Up-Frameshift 1(UPF1) is a key protein factor in the nonsense-mediated mRNA degradation pathway (NMD), its role in carcinogenesis of EEC remains unclear. In this study, we first evaluated the expression level of UPF1 in EEC tissues and cell lines. Then, we investigated the effect of UPF1 on cellular function and mTOR signaling pathway; these effects were further validated in vivo. Finally, its effect on autophagy was evaluated by western blot and GFP-mRFP-LC3 staining. UPF1 expression in the EEC tissue samples was significantly higher than that of matched normal tissue samples. Overexpression of UPF1 promotes migration and invasion of EEC cells. Conversely, depletion of UPF1 suppresses migration and invasion of EEC cells. In addition, overexpression of UPF1 increased the in vivo growth of our EEC xenograft tumor. Finally, UPF1 increased the activity of the mTOR/P70S6K/4EBP1 signaling pathway and inhibited autophagy in EEC cells. These findings suggest that UPF1 functions as an oncogene to promote EEC carcinogenesis. Our findings propose UPF1 as a new potential therapeutic target for EEC. Funding Statement: This study was supported by the Guangdong Science and Technology Department (No.2019A1515012194), The Health and Family Planning Commission of Guangzhou Municipality (No.201707010425)，and Lin He’s Academician Workstation of New Medicine and Clinical Translation. Declaration of Interests: The all authors declare that they have no competing interests. Ethics Approval Statement: All patients provided informed consent, and the study was approved by the ethics committee of Third Affiliated Hospital of Guangzhou Medical University.