Guang Shan1, Xike Zhou2,3, Juan Gu2,3, Daoping Zhou4, Wei Cheng4, Huaiguo Wu4, Yueping Wang4,5, Tian Tang4,6, Xuedong Wang7,8. 1. Department of Urology, RenMin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China. 2. Department of Medical Laboratory Science, The Fifth People's Hospital of Wuxi, Nanjing Medical University, 1215 Guangrui Road, Jiangsu, 214000, Wuxi, People's Republic of China. 3. Department of Pathology, The Fifth People's Hospital of Wuxi, The Medical School of Jiangnan University, Jiangsu, 214000, Wuxi, People's Republic of China. 4. Center for Precision Medicine, Anhui No.2 Provincial People's Hospital, Hefei, 230041, Anhui, People's Republic of China. 5. Department of Biology, College of Arts & Science, Massachusetts University, MA, 02125, Boston, USA. 6. Department of Oncology, RenMin Hospital of Wuhan University, Hubei, 430060, Wuhan, People's Republic of China. 7. Department of Pathology, The Fifth People's Hospital of Wuxi, The Medical School of Jiangnan University, Jiangsu, 214000, Wuxi, People's Republic of China. wxd729@126.com. 8. Center for Precision Medicine, Anhui No.2 Provincial People's Hospital, Hefei, 230041, Anhui, People's Republic of China. wxd729@126.com.
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.
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.
Authors: Julio César Villegas-Pineda; Mélida Del Rosario Lizarazo-Taborda; Adrián Ramírez-de-Arellano; Ana Laura Pereira-Suárez Journal: Front Cell Dev Biol Date: 2021-11-29