Loss of exosomal miR-146a-5p from cancer-associated fibroblasts after androgen deprivation therapy contributes to prostate cancer metastasis.

Abstract

BACKGROUND:

Androgen deprivation therapy (ADT) is the backbone of therapy for advanced prostate cancer (PCa). Despite the good initial response, castration resistance and metastatic progression will inevitably occur. Cancer-associated fibroblasts (CAFs) may be implicated in promoting metastasis of PCa after ADT. Our aim is to investigate the role and mechanism of CAFs-derived exosomes involving in metastasis of PCa after ADT.

METHODS:

PCa cells were co-cultured with exosomes derived from 10 nM dihydrotestosterone (DHT)-treated (simulating the high androgen level of prostate cancer microenvironment) or ethanol (ETOH) -treated (simulating the castration level of prostate cancer microenvironment after ADT) CAFs, and their migration and invasion differences under castration condition were examined both in vitro and in vivo. The miRNA profiles of exosomes derived from DHT-treated CAFs and matched ETOH-treated CAFs were analysed via next generation sequencing. The transfer of exosomal miR-146a-5p from CAFs to PCa cells was identified by fluorescent microscopy. The function and direct target gene of exosomal miR-146a-5p in PCa cells were confirmed through Transwell assays, luciferase reporter, and western blot.

RESULTS:

Compared with DHT-treated CAFs, exosomes derived from ETOH-treated CAFs dramatically increased migration and invasion of PCa cells under castration condition. MiR-146a-5p level in exosomes from ETOH-treated CAFs was significantly reduced. The loss of miR-146a-5p may strengthen the epithelial-mesenchymal transition (EMT) to accelerate cancer cells metastasis by modulating epidermal growth factor receptor (EGFR)/ERK pathway.

CONCLUSIONS:

CAFs-derived exosomal miR-146a-5p confers metastasis in PCa cells under ADT through the EGFR/ERK pathway and it may present a new treatment for PCa.

• Authors: Yu Zhang, Jing Zhao, Mao Ding, Yiming Su, Di Cui, Chenyi Jiang, Sheng Zhao, Gaozhen Jia, Xiaohai Wang, Yuan Ruan, Yifeng Jing, Shujie Xia, Bangmin Han
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 39 Issue 1 Pg. 282 (Dec 14 2020) ISSN: 1756-9966 [Electronic] England
• PMID: 33317606 (Publication Type: Journal Article)

Chemical References

• Androgen Antagonists
• MIRN146 microRNA, human
• MicroRNAs

Topics

• Androgen Antagonists (adverse effects)
• Animals
• Apoptosis
• Cancer-Associated Fibroblasts (drug effects, metabolism, pathology)
• Cell Movement
• Cell Proliferation
• Epithelial-Mesenchymal Transition
• Exosomes (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (chemically induced, genetics, metabolism, secondary)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics)
• Neoplasm Invasiveness
• Prognosis
• Prostatic Neoplasms (drug therapy, pathology)
• Tumor Cells, Cultured
• Tumor Microenvironment
• Xenograft Model Antitumor Assays