Tao Li1, Yingchun Wan2, Ziyuan Su3, Jiayu Li4, Minna Han5, Changyu Zhou6. 1. Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, 130033, Jilin, People's Republic of China. 2. Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun, 130033, Jilin, People's Republic of China. 3. Department of Pharmacy, Changchun Second Hospital, Changchun, 130062, Jilin, People's Republic of China. 4. Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, 130033, Jilin, People's Republic of China. 5. Department of Medcine, Medical School of Chinese People and Apos's Liberation Army, Chinese People and Apos's Liberation Army General Hospital, Beijing, 100853, People's Republic of China. 6. Department of Digestion, China-Japan Union Hospital of Jilin University, No. 126 Xiantai Street, Changchun, 130033, People's Republic of China. drZhouCY1224@163.com.
Abstract
BACKGROUND: Exosomes are potential tools for disease control by regulating intercellular communication through carrying proteins and RNAs between cells or remote organs. Exosome activities have aroused wide concerns in cancer biology and malignancy control. AIMS: This study was performed to explore the roles of mesenchymal stem cell (MSC)-derived exosomes in colorectal cancer (CRC) progression. METHODS: MSC-exosomal microRNAs (miRNAs) in CRC tissues were analyzed, and aberrantly expressed miRNAs in CRC tissues were obtained from the data available on the GEO database. Altered expression of miR-3940-5p was introduced to identify its role in CRC invasion and metastasis in both cell and animal models. The binding relationship between miR-3940-5p and Integrin alpha6 (ITGA6) was predicted on TargetScan and validated through a luciferase assay. The effects of ITGA6 on CRC were figured out. RESULTS: MSC-derived exosomes carried miR-3940-5p into CRC cells. Up-regulation of miR-3940-5p inhibited epithelial-mesenchymal transition (EMT) and invasion of CRC cells, and suppressed the tumor metastasis and growth in vivo. miR-3940-5p was found to directly bind to ITGA6. Overexpression of ITGA6 promoted CRC cell invasion and EMT and tumor progression through upregulating the transforming growth factor-beta1 (TGF-β1) signaling. A TGF-β1-specific antagonist, Disitertide, blocked the functions of ITGA6 both in vivo and in vitro. CONCLUSION: MSC-exosomal miR-3940-5p inhibits invasion and EMT of CRC cells as well as growth and metastasis of tumors through targeting ITGA6 and the following TGF-β1 inactivation. This study may provide novel insights into exosome-based treatment for CRC.
BACKGROUND: Exosomes are potential tools for disease control by regulating intercellular communication through carrying proteins and RNAs between cells or remote organs. Exosome activities have aroused wide concerns in cancer biology and malignancy control. AIMS: This study was performed to explore the roles of mesenchymal stem cell (MSC)-derived exosomes in colorectal cancer (CRC) progression. METHODS: MSC-exosomal microRNAs (miRNAs) in CRC tissues were analyzed, and aberrantly expressed miRNAs in CRC tissues were obtained from the data available on the GEO database. Altered expression of miR-3940-5p was introduced to identify its role in CRC invasion and metastasis in both cell and animal models. The binding relationship between miR-3940-5p and Integrin alpha6 (ITGA6) was predicted on TargetScan and validated through a luciferase assay. The effects of ITGA6 on CRC were figured out. RESULTS: MSC-derived exosomes carried miR-3940-5p into CRC cells. Up-regulation of miR-3940-5p inhibited epithelial-mesenchymal transition (EMT) and invasion of CRC cells, and suppressed the tumor metastasis and growth in vivo. miR-3940-5p was found to directly bind to ITGA6. Overexpression of ITGA6 promoted CRC cell invasion and EMT and tumor progression through upregulating the transforming growth factor-beta1 (TGF-β1) signaling. A TGF-β1-specific antagonist, Disitertide, blocked the functions of ITGA6 both in vivo and in vitro. CONCLUSION: MSC-exosomal miR-3940-5p inhibits invasion and EMT of CRC cells as well as growth and metastasis of tumors through targeting ITGA6 and the following TGF-β1 inactivation. This study may provide novel insights into exosome-based treatment for CRC.