Drug Design, Development and Therapy (Mar 2020)
miR-370-3p Alleviates Ulcerative Colitis-Related Colorectal Cancer in Mice Through Inhibiting the Inflammatory Response and Epithelial-Mesenchymal Transition
Abstract
Lianjie Lin,1 Dongxu Wang,1 Suxuan Qu,1 Hong Zhao,1,2 Yan Lin1 1Department of Gastroenterology and Hepatology, Shengjing Hospital of China Medical University, Shenyang 110004, People’s Republic of China; 2Department of Gastroenterology, The Second Affiliated Hospital of Shenyang Medical College, Shenyang 110035, People’s Republic of ChinaCorrespondence: Yan LinDepartment of Gastroenterology and Hepatology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, People’s Republic of ChinaTel/Fax +86-24-96615-26211Email [email protected]: Ulcerative colitis (UC) is a chronic and inflammatory bowel disease. UC-associated colorectal cancer (UC-CRC) is one of the most severe complications of long-standing UC. In the present study, we explored the effects of miR-370-3p on UC-CRC in vivo and investigated its underlying mechanisms in vivo and in vitro.Methods: Azoxymethane (AOM) and dextran sodium sulfate (DSS) were used to induce UC-CRC in C57BL/6 mice. AOM/DSS-induced mice were treated with 5× 108 pfu miR-370-3p overexpressing-adenovirus via tail-vein injection every two weeks.Results: We found that miR-370-3p significantly improved the body weights and survival rates and inhibited the tumorigenesis of UC-CRC in AOM/DSS mice. Mechanically, miR-370-3p inhibited AOM/DSS-induced inflammatory response by decreasing tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) through targeting toll-like receptor 4 (TLR4), as demonstrated by down-regulation of TLR4, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and phosphorylated epidermal growth factor receptor (pEGFR). miR-370-3p decreased the expression of tumor-associated proteins, including p53, β-catenin, and ki67 in AOM/DSS-treated mice. Additionally, miR-370-3p remarkably inhibited epithelial-mesenchymal transition (EMT) via increasing E-cadherin expression and reducing N-cadherin and Vimentin expression in vivo. Further studies showed that miR-370-3p repressed proliferation and EMT of colon cancer cells in vitro. Moreover, we proved that miR-370-3p decreased the expression of tumor-associated proteins and reversed EMT by regulating β-catenin in colon cancer cells.Conclusion: Taken together, miR-370-3p alleviated UC-CRC by inhibiting the inflammatory response and EMT in mice, which suggested miR-370-3p as a novel potential target for UC-CRC therapy.Keywords: ulcerative colitis-associated colorectal cancer, azoxymethane/dextran sodium sulfate, inflammatory response, epithelia-mesenchymal transition, carcinogenesis
