期刊
CELL DEATH AND DIFFERENTIATION
卷 24, 期 12, 页码 2199-2209出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2017.151
关键词
-
资金
- National Key R&D Program of China [2016YFC1302300, 2014CB910600]
- National Natural Science Foundation of China [81772609, 81472549, 31521091]
miR-148a has been shown to regulate inflammation, immunity and the growth of certain tumors, but its roles in colitis and colorectal tumorigenesis remain largely undetermined. Here we found miR-148a-deficient mice to be more susceptible to colitis and colitis-associated tumorigenesis. Both were associated with increased nuclear factor kappa B (NF-kappa B) and signal transducer and activator of transcription 3 (STAT3) signaling. Bone marrow- and non-bone marrow-derived miR-148a contributed to colitis and colitis-associated tumorigenesis. miR-148a loss of heterozygosity exacerbated Apc(min/+) colon and small intestinal spontaneous tumor development. Restoring miR-148a expression prevented both spontaneous and carcinogen-induced colon tumor development. miR-148a was downregulated in human inflammatory bowel disease (IBD) and colorectal cancer patient tissues. This correlated with a high degree of miR-148a promoter methylation mediated by a complex comprised of P65 and DNA methyltransferase 3 alpha (DNMT3A). miR-148a directly targets several well-accepted upstream regulators of NF-kappa B and STAT3 signaling, including GP130, IKK alpha, IKK beta, IL1R1 and TNFR2, which leads to decreased NF-kappa B and STAT3 activation in macrophages and colon tissues. Our findings reveal that miR-148a is an indirect tumor suppressor that modulates colitis and colitis-associated tumorigenesis by suppressing the expression of signaling by NF-kappa B and STAT3 and their pro-inflammatory consequences.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据