CAFs-EVs-miR-6765-3p promotes malignant progression of colorectal cancer by regulating aerobic glycolysis mediated by the GNG7/mTOR pathway.

Recently, the signaling interactions between cancer cells and stromal cells within the tumor microenvironment (TME) have been extensively studied. Cancer-associated fibroblasts (CAFs) serve as critical stromal components in the TME. Numerous studies have shown that CAFs promote cancer progression by delivering microRNAs (miRNAs) to colorectal cancer (CRC) cells. In this study, miR-6765-3p was found to be overexpressed in extracellular vesicles (EVs) secreted by CAFs (CAFs-EVs) and could be transferred to CRC cells, thereby enhancing malignant cell phenotypes. Further experiments have demonstrated that miR-6765-3p directly targets the 3'-untranslated region (UTR) of G protein γ 7 (GNG7). Mechanistically, we have collaboratively demonstrated through cellular and animal experiments that the overexpression of GNG7 reduces CRC progression mediated by miR-6765-3p in CAFs-EVs. Furthermore, GNG7 has been elucidated to suppress CRC development by inhibiting the phosphorylation of proteins involved in the mTOR pathway. It is important to emphasize that the mTOR pathway plays a key role in regulating aerobic glycolysis processes in cancer. Consistently, our study further demonstrated that CAFs-EVs activate aerobic glycolysis via the mTOR pathway by suppressing GNG7 expression. In summary, our findings suggest that CAFs-EVs carrying miR-6765-3p promote the malignant progression of CRC by modulating the GNG7/mTOR pathway to stimulate aerobic glycolysis.