Cancer-Associated Fibroblast–Derived miR-146a-5p Generates a Niche That Promotes Bladder Cancer Stemness and Chemoresistance

Abstract

Cancer stem-like cells (CSCs) play pivotal roles in both chemoresistance and recurrence of many cancer types, including urothelial bladder cancer (UBC). In addition to intrinsic signaling pathways, extracellular cues from the tumor microenvironment (TME) are indispensable for the maintenance of CSCs. To better understand the mechanisms involved in TME-mediated generation and support of UBC CSCs, we focused on the role of cancer-associated fibroblasts (CAFs) in this study. Overexpression of miR-146a-5p in CAFs promoted CAF-to-UBC cell interactions, cancer stemness, and chemoresistance to treatment with gemcitabine and cisplatin. Mechanistically, miR-146-5p upregulated SVEP1 in CAFs by enhancing the recruitment of transcriptional factor YY1. Meanwhile, by targeting the 3’UTR of mRNAs of ARID1A and PRKAA2 (also known as AMPKα2) in UBC cells, CAF-secreted miR-146a-5p promoted cancer stemness and chemoresistance. Downregulation of ARID1A resulted in the inhibition of SOCS1 and subsequent STAT3 activation, and downregulated PRKAA2 led to the activation of mTOR signaling. Elevated levels of exosomal miR-146a-5p in the serum of UBC patients were correlated with both tumor stage and relapse risk. These findings altogether indicate that CAF-derived miR-146a-5p can promote stemness and enhance chemoresistance in UBC. Exosomal miR-146a-5p may be a biomarker of UBC recurrence and a potential therapeutic target.

Taurine Inhibits Ferroptosis Mediated by the Crosstalk between Tumor Cells and Tumor‐Associated Macrophages in Prostate Cancer

“…Fluorescence Microscopy: M0 macrophages (1 × 10 7 ) were seeded on coverslips in a 24-well plate and cocultured with PKH67 (Sigma, PKH67GL)-labeled EVs or EVs containing Cy3 labeled miR-181a-5p (miR-181a-5p-Cy3) at 37 °C for 4 h. [40] Specimens were counterstained with DAPI (Sigma, D9542) and mounted with DAPI containing media (Biosharp, BL739A). All images were captured with a microscope (Leica, DFC420C).…”

Role of Exosomes in Cancer and Aptamer-Modified Exosomes as a Promising Platform for Cancer Targeted Therapy

“…There is mounting evidence indicating that TME-derived exosomes are involved in the regulation of CSCs in different types of cancers through delivering the long non-coding RNA (lncRNA) H19 [ 88 ]. Recently, Zhuang et al provided evidence demonstrating that cancer-associated fibroblasts (CAFs) could help to form a favorable niche to promote bladder cancer stemness via exosomes-mediated transfer of miR-146a-5p [ 89 ]. As key components of the TME in solid tumors, tumour-associated macrophages (TAMs) participate in regulating multiple aspects of tumorigenesis from genetic instability through to metastasis and tumour immunity [ 90 ].…”

“…Other exosomal cargos including lncRNA H19 [ 357 ] and circ_0001610 [ 358 ] were also reported to promote stemness and chemoresistance of CRC through different mechanisms. Moreover, in bladder cancer, CAFs-derived miR-146a-5p was demonstrated to foster CSC niche formation and cancer stemness to drive chemoresistance via co-targeting ARID1A and PRKAA2 (also known as AMPKα2) [ 89 ]. Given these findings, the therapeutic strategy to overcome drug resistance through targeting exosomes-induced EMT and CSCs is attracting much interest [ 47 , 359 ].…”

Targeting drug‐tolerant cells: A promising strategy for overcoming acquired drug resistance in cancer cells

“…It is now evident that the TME plays a pivotal role in tumor growth, progression, metastasis, and response to anticancer treatments 249–255 . The TME components consist of an extracellular matrix (ECM) and multiple cell types including cancer‐associated fibroblasts (CAFs), tumor‐associated macrophages (TAMs), endothelial cells, and mesenchymal stem cells (MSCs) 256 .…”