Cancer-associated fibroblasts exosomes promote prostate cancer metastasis through miR-500a-3p/FBXW7/HSF1 axis under hypoxic microenvironment

Abstract

Metastasis is the main cause of deaths in prostate cancer (PCa). However, the mechanisms of PCa metastasis remain unknown. In this study, severe hypoxia was identified in primary lesions of metastasis PCa (mPCa). The exosomes secreted by cancer-associated fibroblasts (CAFs) significantly promoted PCa metastasis in vitro and in vivo. miRNA sequencing analysis and reverse transcription quantitative PCR (RT-qPCR) experiments indicated miR-500a-3p was significantly increased in CAFs exosomes under hypoxia. RT-qPCR, western blotting, and dual luciferase reporter assays were used to identify FBXW7 was a target of miR-500a-3p. Using immunohistochemistry, we found a decrease in FBXW7 expression with PCa progression, while there was an increase in HSF1 expression. After FXBW7 plasmid transfection, the metastasis ability was suppressed and HSF1 expression significantly decreased in PCa cells. These data indicated that CAFs exosomes promote PCa metastasis through miR-500a-3p/FBXW7/HSF1 axis under hypoxic microenvironment. Targeting hypoxia or exosomal miR-500a-3pmay provide a potential treatment strategy for the management of PCa.