Journal
GUT
Volume 65, Issue 9, Pages 1470-+Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2014-308455
Keywords
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Categories
Funding
- National Natural Science Foundation of China [81230057, 81472262, 81200264, 81372615]
- National High Technology Research and Development Program (863 Program) [2014AA020803]
- National Science and Technology Major Projects [2013ZX09103003-016]
- Shanghai Science and Technology Development Fund [12140902300, 12410707400]
- Shanghai Health System Outstanding Young Talent Training Plan [XYQ2013118]
- Emerging cutting-edge technology joint research projects of Shanghai [SHDC12012106]
- Tongji University outstanding youth programme [1501219074]
- National Cancer Institute, National Institutes of Health [R01 CA72851, CA181572, CA184792]
- Baylor Research Institute
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Objective miR-21 was found to be overexpressed in the colon tissues and serum of patients with UC and colorectal cancer (CRC); however, the exact roles of miR-21 in colitis-associated CRC remain unclear. The aim of our study was to investigate the biological mechanisms of miR-21 in colitis-associated colon cancer (CAC). Design miR-21 expression was examined in the tumours of 62 patients with CRC from China and 37 colitis-associated neoplastic tissues from Japan and Austria. The biological functions of miR-21 were studied using a series of in vitro, in vivo and clinical approaches. Results miR-21 levels were markedly upregulated in the tumours of 62 patients with CRC, 22 patients with CAC, and in a mouse model of CAC. Following azoxymethane and dextran sulfate sodium intervention, miR-21-knockout mice showed reduced expression of proinflammatory and procarcinogenic cytokines (interleukin (IL) 6, IL-23, IL-17A and IL-21) and a decrease in the size and number of tumours compared with the control mouse group. The absence of miR-21 resulted in the reduced expression of Ki67 and the attenuated proliferation of tumour cells with a simultaneous increase in E-cadherin and decrease in beta-catenin and SOX9 in the tumours of CAC mice. Furthermore, the absence of miR-21 increased the expression of its target gene PDCD4 and subsequently modulated nuclear factor (NF)-kappa B activation. Meanwhile, miR-21 loss reduced STAT3 and Bcl-2 activation, causing an increase in the apoptosis of tumour cells in CAC mice. Conclusions These observations provide novel evidence for miR-21 blockade to be a key strategy in reducing CAC.
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