Mesenchymal Stem Cell-Derived Exosomal microRNA-3940-5p Inhibits Colorectal Cancer Metastasis by Targeting Integrin α6

Colorectal Cancer
16/07/2020

Dig Dis Sci. 2020 Jul 15. doi: 10.1007/s10620-020-06458-1. Online ahead of print.

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.