Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3
Abstract Background Cancer-associated fibroblasts (CAFs) have been intensively studied in recent studies with aims of finding more concrete evidence on their mechanism of involvement in tumor progression, which is currently unknown. CAFs can secrete exosomes which are loaded with proteins, lipids an...
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doaj-59f8f9e5cfd54e4693128059cc3627fb2020-11-25T02:27:47ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662020-04-0139111510.1186/s13046-019-1507-2Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3Xijuan Chen0Junqi Liu1Qinglan Zhang2Baoxing Liu3Yan Cheng4Yonglei Zhang5Yanan Sun6Hong Ge7Yingqiang Liu8Department of Radiation Oncology, the Affiliated Tumor Hospital of Zhengzhou UniversityDepartment of Radiation Oncology, the First Affiliated Hospital of Zhengzhou UniversityDepartment of Hematology, the Affiliated Tumor Hospital of Zhengzhou UniversityDepartment of Chest Surgery, the Affiliated Tumor Hospital of Zhengzhou UniversityDepartment of Gynecology, the First Affiliated Hospital of Zhengzhou UniversityDepartment of General Surgery, the Affiliated Tumor Hospital of Zhengzhou UniversityDepartment of Radiation Oncology, the Affiliated Tumor Hospital of Zhengzhou UniversityDepartment of Radiation Oncology, the Affiliated Tumor Hospital of Zhengzhou UniversityDepartment of General Surgery, the Affiliated Tumor Hospital of Zhengzhou UniversityAbstract Background Cancer-associated fibroblasts (CAFs) have been intensively studied in recent studies with aims of finding more concrete evidence on their mechanism of involvement in tumor progression, which is currently unknown. CAFs can secrete exosomes which are loaded with proteins, lipids and RNAs, all of which affect tumor microenvironment. The present study identified microRNA-93-5p (miR-93-5p) as a novel exosomal cargo responsible for the pro-tumorigenic effects of CAFs on colorectal cancer (CRC). Methods CAFs and normal fibroblasts (NFs) were isolated from cancerous tissues and matched with paracancerous tissues that had been surgically resected from CRC patients. The interaction among miR-93-5p, forkhead box A1 (FOXA1) and TGFB3 was identified through ChIP and dual luciferase reporter assays. The proliferation and apoptosis of SW480 cells co-cultured with CAFs-derived exosomes under irradiation were evaluated by CCK-8, colony formation, and flow cytometric assays. Tumorigenesis of SW480 cells in nude mice was assessed under the irradiation. Results FOXA1 was found to be associated with reduced radioresistance in CRC cells and was verified as a target of miR-93-5p. CAFs-derived exosomes contained higher miR-93-5p than those from NFs, which augmented SW480 cell proliferation and rescued them from radiation-induced apoptosis. miR-93-5p was identified as a mediator of the exosomal effects of CAFs on SW480 cells, possibly through downregulating FOXA1 and upregulating TGFB3. FOXA1 could bind to the promoter of TGFB3, thereby inhibiting nuclear accumulation of TGFB3. Also, CAFs-derived exosomes containing miR-93-5p increased the tumor growth of SW480 cells in irradiated nude mice. Conclusion The present study identifies miR-93-5p as a specific exosomal cargo that rescues CRC cells against radiation-induced apoptosis.http://link.springer.com/article/10.1186/s13046-019-1507-2Colorectal cancerCancer-associated fibroblastsmicroRNA-93-5pFOXA1TGFB3Radioresistance |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xijuan Chen Junqi Liu Qinglan Zhang Baoxing Liu Yan Cheng Yonglei Zhang Yanan Sun Hong Ge Yingqiang Liu |
spellingShingle |
Xijuan Chen Junqi Liu Qinglan Zhang Baoxing Liu Yan Cheng Yonglei Zhang Yanan Sun Hong Ge Yingqiang Liu Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3 Journal of Experimental & Clinical Cancer Research Colorectal cancer Cancer-associated fibroblasts microRNA-93-5p FOXA1 TGFB3 Radioresistance |
author_facet |
Xijuan Chen Junqi Liu Qinglan Zhang Baoxing Liu Yan Cheng Yonglei Zhang Yanan Sun Hong Ge Yingqiang Liu |
author_sort |
Xijuan Chen |
title |
Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3 |
title_short |
Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3 |
title_full |
Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3 |
title_fullStr |
Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3 |
title_full_unstemmed |
Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3 |
title_sort |
exosome-mediated transfer of mir-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating foxa1 and upregulating tgfb3 |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2020-04-01 |
description |
Abstract Background Cancer-associated fibroblasts (CAFs) have been intensively studied in recent studies with aims of finding more concrete evidence on their mechanism of involvement in tumor progression, which is currently unknown. CAFs can secrete exosomes which are loaded with proteins, lipids and RNAs, all of which affect tumor microenvironment. The present study identified microRNA-93-5p (miR-93-5p) as a novel exosomal cargo responsible for the pro-tumorigenic effects of CAFs on colorectal cancer (CRC). Methods CAFs and normal fibroblasts (NFs) were isolated from cancerous tissues and matched with paracancerous tissues that had been surgically resected from CRC patients. The interaction among miR-93-5p, forkhead box A1 (FOXA1) and TGFB3 was identified through ChIP and dual luciferase reporter assays. The proliferation and apoptosis of SW480 cells co-cultured with CAFs-derived exosomes under irradiation were evaluated by CCK-8, colony formation, and flow cytometric assays. Tumorigenesis of SW480 cells in nude mice was assessed under the irradiation. Results FOXA1 was found to be associated with reduced radioresistance in CRC cells and was verified as a target of miR-93-5p. CAFs-derived exosomes contained higher miR-93-5p than those from NFs, which augmented SW480 cell proliferation and rescued them from radiation-induced apoptosis. miR-93-5p was identified as a mediator of the exosomal effects of CAFs on SW480 cells, possibly through downregulating FOXA1 and upregulating TGFB3. FOXA1 could bind to the promoter of TGFB3, thereby inhibiting nuclear accumulation of TGFB3. Also, CAFs-derived exosomes containing miR-93-5p increased the tumor growth of SW480 cells in irradiated nude mice. Conclusion The present study identifies miR-93-5p as a specific exosomal cargo that rescues CRC cells against radiation-induced apoptosis. |
topic |
Colorectal cancer Cancer-associated fibroblasts microRNA-93-5p FOXA1 TGFB3 Radioresistance |
url |
http://link.springer.com/article/10.1186/s13046-019-1507-2 |
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