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 CAF-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 increase 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

Enhancement of acellular cartilage matrix scaffold by Wharton's jelly mesenchymal stem cell-derived exosomes to promote osteochondral regeneration

“…The lipid outer membrane of Exos can protect the various encapsulated nucleic acids, proteins, lipids and other signaling molecules, enabling them to facilitate intercellular communication. Among these cargos, exosomal microRNAs (miRNAs) are believed to play an important role in the biological processes of tumor immunity [ 11 ], the inflammatory response and oxidative damage [ 12 ], apoptosis [ 13 ], and cancer metastasis [ 14 ]. Recent evidence has shown that Exos derived from MSCs (MSC-Exos) have similar biological functions to MSCs and play an important role in MSC-mediated tissue repair and regeneration [ [15] , [16] , [17] ].…”

Apaf‐1 interacting protein, a new target of microRNA‐146a‐3p, promotes prostate cancer cell development via the ERK1/2 pathway

“…Thus, we considered that the effects of miR‐146a‐3p on cell viability and motility are associated with the ERK1/2 signaling pathway in PCa. Consistent with this, a comprehensive analysis of PCa reported that the EGFR/ERK1/2 pathway (Zhang et al, 2020) is controlled by miR‐146, which mediates tumor suppression. However, this study had certain limitations.…”

Cervical Cancer Cells-Derived Extracellular Vesicles Containing microRNA-146a-5p Affect Actin Dynamics to Promote Cervical Cancer Metastasis by Activating the Hippo-YAP Signaling Pathway via WWC2

“…Furthermore, evidence has been presented demonstrating an enrichment of miR-146a-5p in the EVs secreted by cervical cancer cells. Similarly, miR-146a-5p in EVs from cancer-associated fibroblasts can enhance EMT to accelerate prostate cancer cell metastasis [27]. In addition, it is reported that breast cancer-derived EVs carrying miR-146a contributed to the invasion and metastasis of breast cancer cells through activating cancerassociated fibroblasts [28].…”