Extracellular vesicles derived from cancer-associated fibroblasts carry tumor-promotive microRNA-1228-3p to enhance the resistance of hepatocellular carcinoma cells to sorafenib.

Abstract

Cancer-associated fibroblasts (CAFs)-derived extracellular vesicles (EVs) can promote tumor progression by delivering microRNA (miRNA). Whether EVs could transfer miR-1228-3p into hepatocellular carcinoma (HCC) cells to affect chemoresistance was discussed in this study. Normal fibroblasts (NFs) and CAFs were isolated from tissue samples of HCC patients. We assessed the functions of HCC cells after co-culturing with NFs and CAFs. miR-1228-3p gain-of-function experiments were conducted. Next, functional assays were carried out to determine the binding of miR-1228-3p to placenta associated 8 (PLAC8). In vivo models were constructed for validation. CAFs-derived EVs exerted promoting effect on proliferative, migrating, invading potential of HCC cells and their resistance to sorafenib. PLAC8 was demonstrated as a direct target of miR-1228-3p. By targeting PLAC8, miR-1228-3p activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In addition, the transfer of miR-1228-3p from CAFs-derived EVs into HCC cells boosted chemoresistance of HCC cells, which was reversed by restoring PLAC8. All in all, CAF-EV-carried miR-1228-3p strengthens the chemoresistance of HCC through activating PLAC8-mediated PI3K/AKT pathway. This finding contributes to the development of EV-based therapies overcoming the chemoresistance of HCC.