Downregulated exosomal microRNA-148b-3p in cancer associated fibroblasts enhance chemosensitivity of bladder cancer cells by downregulating the Wnt/β-catenin pathway and upregulating PTEN

Abstract

Objective Exosomes derived from cancer-associated fibroblasts (CAFs) are known as important drivers of tumor progression. Previously, microRNA (miR)-148b-3p has been found to be upregulated in bladder cancers as well as in body fluids (blood, urine) of bladder cancer patients. Here, we aimed to explore the role of CAF-derived exosome miR-148b-3p in bladder cancer progression and chemosensitivity. Methods Transwell, MTT, flow cytometry and colony formation assays were applied to assess the effects of CAF-derived exosomes on bladder cancer cell metastasis, epithelial-mesenchymal transition (EMT) and chemosensitivity. A dual luciferase reporter assay was employed to evaluate the targeting relationship between miR-148b-3p and PTEN. Gain- and loss- of function assays were conducted to explore the roles of miR-148b-3p and PTEN in the behavior of bladder cancer cells. The role of PTEN in the metastasis, EMT and chemosensitivity of bladder cancer cells was assessed both in vivo and in vitro. Results We found that CAF-derived exosomes promoted the metastasis, EMT and drug resistance of bladder cancer cells. We also found that CAF-derived exosomes could directly transport miR-148b-3p into bladder cancer cells. In a xenograft mouse model we found that CAF-derived exosomes increased miR-148b-3p expression levels and promoted tumor proliferation, metastasis and drug resistance. PTEN was validated as a target of miR-148b-3p. Concordantly, we found that PTEN overexpression inhibited EMT, metastasis and chemoresistance in bladder cancer cells, reversing the tumor promoting effects of miR-148b-3p via the Wnt/β-catenin pathway. Conclusions Our results suggest that miR-148b-3p downregulation in CAF-derived exosomes, thereby inhibiting the Wnt/β-catenin pathway and promoting PTEN expression, may offer potential opportunities for bladder cancer treatment.

CCDC137 Is a Prognostic Biomarker and Correlates With Immunosuppressive Tumor Microenvironment Based on Pan-Cancer Analysis

“…Increasing evidence has revealed their clinicopathological significance in predicting outcomes and therapeutic efficacy ( Greten and Grivennikov, 2019 ; Vitale et al, 2019 ; Suzuki et al, 2021 ). TAMs and CAFs in TME always accelerate tumor progression ( Akins et al, 2020 ; Liu et al, 2021 ; Shan et al, 2021 ). Our results revealed that CCDC137 have close relationships with TAMs and CAFs infiltration in most tumor types.…”

Biological Roles and Clinical Significance of Exosome-Derived Noncoding RNAs in Bladder Cancer

“…Some exosomal miRNAs have been identified to initiate or prevent EMT processes in BCa through the Wnt/β-catenin signaling pathway. Exosomal miR-148b-3p is secreted by cancer-associated fibroblasts and is transmitted into BCa cells and acts as a tumor promotor to trigger EMT initiation by interacting with the PTEN gene ( 64 ). Unlike miR-148b-3p, Li et al.…”

“…By examining the sensitivity of BCa cells to Paclitaxel (PTX) and doxorubicin (DOX), Shan et al. demonstrated that after treatment, exosomes derived from cancer-associated fibroblasts, T24 and 5367 cells, showed lower levels of apoptosis, indicating exosomal miR-148b-3p contributed to the reduction in chemosensitivity ( 64 ). Liang et al.…”

Exosomes in Cancer Diagnosis and Radiation Therapy

“…Several studies have demonstrated that exosomal activity might be involved in chemo-resistance. In EMT, Shan et al indicated that downregulation of exosomal miR-148b-3p may offer opportunities in the treatment of bladder cancer by increasing chemosensitivity via inhibition of the Wnt/β-catenin pathway and promoting expression of PTEN [95]. In addition to it, Liu et al reported that exosome-transmitted miR-128-3p increased chemosensitivity of oxaliplatin-resistant colorectal cancer by suppressing epithelial-mesenchymal transition and inducing drug accumulation in cancer cells [96].…”