EMC3 as a Novel Biomarker and Driver of PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma Progression

Endoplasmic reticulum membrane protein complex subunit 3 (EMC3) plays a critical role in protein translocation and processing and has been implicated in multiple cancer types. However, its specific function and clinical relevance in hepatocellular carcinoma (HCC) remain poorly understood. This study aimed to investigate the molecular role and prognostic significance of EMC3 in HCC progression.

Public datasets and clinical samples from HCC patients were analyzed to assess EMC3 expression and its association with prognosis. Genomic and immunomic profiles were evaluated to explore EMC3-related genomic instability and its regulation of the tumor immune microenvironment (TIME). Functional assays, including clone formation, CCK-8, EdU proliferation, wound healing, Transwell migration and invasion, and in vivo xenograft and lung metastasis models, were performed to examine the effects of EMC3 on HCC cell proliferation and epithelial-mesenchymal transition (EMT). Mechanistic studies involved RNA sequencing, pathway enrichment analysis, and rescue experiments using the PI3K inhibitor LY294002.

EMC3 was significantly overexpressed in HCC tissues and correlated with poor patient survival. Genomic analyses revealed EMC3-associated instability, and immunomic profiling indicated its role in shaping an immunosuppressive TIME. In vitro and in vivo experiments demonstrated that EMC3 promotes HCC proliferation, migration, invasion, and metastasis. Mechanistically, EMC3 activated the PI3K/AKT/mTOR signaling pathway, and inhibition of this pathway reversed the oncogenic effects of EMC3.

EMC3 drives HCC progression by activating the PI3K/AKT/mTOR pathway and modulating the TIME. It represents a novel prognostic biomarker and a potential therapeutic target for HCC, with implications for patient stratification and personalized treatment strategies.