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

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.

Extracellular Vesicles in Advanced Prostate Cancer: Tools to Predict and Thwart Therapeutic Resistance

“…This induced resistance was due to miR-27a derived exosomes that regulated the expression of Trp53 [99]. A third study showed that CAF-secreted exosomal miR-423-5p promoted resistance to docetaxel or bicalutamide in PCa cells LNCaP, 22RV1 and C4-2 cells, respectively, by targeting GREM2 [100].…”

TGF-β Signaling and Resistance to Cancer Therapy

“…Similar to what was observed in cases of chemo-resistance against DNA damaging agents, miRNAs are involved in the activation of TGF-β signaling in cells treated with anti-metabolites and anti-microtubule drugs. Examples of miRNA regulators of TGF-β signaling include miR-423-5p, miR-552, and miR-17–92 cluster (miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a) in prostate cancer, colorectal cancer, and pancreatic cancer ( Cioffi et al, 2015 ; Zhao et al, 2019 ; Shan et al, 2020 ). Intriguingly, TGF-β/SMAD signaling activation directly induced G1 cell-cycle arrest in SCC cells, leading to the entry of tumor-propagating cancer cells (TPCs) into quiescence, which protected cancer cells from DNA damage caused by 5-FU treatment by adopting a condensed heterochromatic state ( Brown et al, 2017 ).…”

The Role of Cancer-Associated Fibroblast as a Dynamic Player in Mediating Cancer Stemness in the Tumor Microenvironment

“…Additionally, exosomal miR-92a-3p derived from colorectal CAF targets anti-tumor F-box/WD repeat-containing protein 7 (FBXW7) and a modulator of apoptosis 1 (MOAP1), thereby endowing chemoresistance to cancer cells ( Hu et al, 2019 ). In line, exosomal miRNA was demonstrated to confer chemoresistance in prostate cancer ( Shan et al, 2020 ) and head and neck cancer ( Qin et al, 2019 ). CAF-derived exosomal long non-coding RNA (lncRNA) H19 was exhibited to enable stemness expression by sponging miR-141 that targets β-catenin ( Ren et al, 2018 ).…”