Cancer-associated fibroblast-secreted exosomal miR-423-5p promotes chemotherapy resistance in prostate cancer by targeting GREM2 through the TGF-\u03b2 signaling pathway

Guang Shan,Xuedong Wang,Tian Tang,Yueping Wang,Daoping Zhou,Wei Cheng,Juan Gu,Lingxun Li

doi:10.1038/s12276-020-0431-z

Abstract

Therapeutic failure in prostate cancer (PC) is believed to result from its unusually invasive and metastatic nature. Cancer-associated fibroblasts (CAFs) are essential in the tumor microenvironment. We intended to study the role of CAF-derived exosomes in the context of PC and the potential regulatory mechanism associated with miR-423-5p and GREM2. CAF-derived exosomes decreased the chemosensitivity of parental PC cells and enhanced the drug resistance of drug-resistant cells. PC-associated fibroblast-derived exosomes carrying miR-423-5p increased the resistance of PC to taxane by inhibiting GREM2 through the TGF-β pathway. Inhibition of the TGF-β pathway partially reversed the increased drug resistance in PC cells induced by CAF-derived exosomes. Inhibition of miR-423-5p enhanced the drug sensitivity of PC cells in vivo. We showed that CAF-secreted exosomal miR-423-5p promoted chemotherapy resistance in PC by targeting GREM2 through the TGF-β pathway. This study may allow the development of novel approaches for PC.

Highlights

Prostate cancer (PC) is the 2nd most common cancer and the 5th most common cause of death[1]
To verify the effect of miR-423-5p on GRAM2 expression, we determined the GREM2 levels in the PC cells treated with the Cancer-associated fibroblasts (CAFs)-derived exosomes, and the results showed that the GREM messenger RNAs (mRNAs) and protein levels in the PC cells treated with the CAF-derived exosomes were significantly decreased, while obvious changes were observed in the PC cells after exosomal miR-423-5p was decreased (P < 0.05, Fig. 5c, d)
Our research demonstrated that miR423-5p was upregulated in the CAF-derived exosomes and that miR-423-5p could promote chemotherapy resistance in PC by targeting GREM2 through the transforming growth factor-β (TGF-β) pathway

Summary

Introduction

Prostate cancer (PC) is the 2nd most common cancer and the 5th most common cause of death[1]. Statistics show that there are 1.6 million males with PC, and 366,000 males die from PC each year[2]. Many factors, including age, race, and family heritability, have been associated with PC development[3]. Based on the severity of this disease, current treatment approaches for PC include hormones, bone-directed treatment, therapeutic vaccines, radiation, and surgery[4]. These treatments can significantly delay or inhibit PC progression, chemotherapy resistance usually leads to death[5].

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Results

Conclusion