Human bone marrow mesenchymal stem cells-derived exosomes attenuated prostate cancer progression via the miR-99b-5p/IGF1R axis

Abstract

ABSTRACT MicroRNA-99b-5p (miR-99b-5p) has been shown to be enriched in serum exosomes of prostate cancer (PCa) patients treated with radiotherapy, while its function in PCa progression remains unclear. The expression levels of miR-99b-5p in PCa tissues, cancer cell lines and human bone marrow mesenchymal stem cells (HBMSCs), as well as HBMSCs-derived exosomes were assessed by quantitative real-time PCR (qRT-PCR). MiR-99b-5p mimics or inhibitor was transfected into HBMSCs, and HBMSCs-derived exosomes with abnormal expression of miR-99b-5p were used to stimulate PCa cell-line LNCaP cells. Cell proliferative rate was evaluated using Cell Counting Kit-8 (CCK-8) and 5‐ethynyl‐2′‐deoxyuridine (EdU) staining assays. Cell migration and invasion were analyzed by Transwell assay. The epithelial-mesenchymal transition (EMT) was evaluated by detecting EMT-related markers using Western blot analysis. The animal model was constructed to confirm the function of miR-99b-5p in vivo. The expression levels of MiR-99b-5p were decreased in PCa tissues and cell lines, while elevated in HBMSCs-derived exosomes. HBMSCs-derived exosomes significantly inhibited cell malignant phenotypes of PCa cells, and miR-99b-5p mimics transfected HBMSCs further enhanced the inhibitory effects of HBMSCs on PCa progression. In addition, miR-99b-5p inhibitor transfected HBMSCs-derived exosomes promoted the progression of PCa in vitro. Insulin-like growth factor 1 receptor (IGF1R) was identified as a downstream target of miR-99b-5p. Moreover, miR-99b-5p mimics transfected HBMSCs obviously inhibited tumor progression by downregulating IGF1R in animal model in vivo. Our results demonstrated that HBMSCs could attenuate PCa progression, and exosomal miR-99b-5p and IGF1R participated in the regulatory process, contributing to our understanding of the pathogenic mechanism of PCa.