科学研究
20170929 miR-148a inhibits colitis and colitis-associated tumorigenesis in mice.
发布时间:2017-09-30  来源:  阅读次数:

Cell Death Differ.2017 Sep 29. doi: 10.1038/cdd.2017.151. [Epub ahead of print]

miR-148a inhibits colitis and colitis-associated tumorigenesis in mice.

Zhu Y1,2,Gu L1,2,Li Y1,2,Lin X1,2,Shen H1,2,Cui K1,2,Chen L1,2,Zhou F3,4,Zhao Q3,4,Zhang J5,Zhong B1,2,Prochownik E6,7,Li Y1,2.

Abstract

miR-148ahas been shown to regulate inflammation, immunity and the growth of certain tumors, but its roles in colitis and colorectaltumorigenesis 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 κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling. Bone marrow- and non-bone marrow-derived miR-148a contributed to colitis and colitis-associatedtumorigenesis. miR-148a loss of heterozygosity exacerbated Apcmin/+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 ofmiR-148a promoter methylation mediated by a complex comprised of P65 and DNA methyltransferase 3 alpha (DNMT3A). miR-148adirectly targets several well-accepted upstream regulators of NF-κB and STAT3 signaling, including GP130, IKKα, IKKβ, IL1R1 and TNFR2, which leads to decreased NF-κB and STAT3 activation in macrophages and colon tissues. Our findings reveal that miR-148ais an indirect tumor suppressor that modulates colitis and colitis-associated tumorigenesis by suppressing the expression of signaling by NF-κB and STAT3 and their pro-inflammatory consequences.Cell Death and Differentiation advance online publication, 29 September 2017; doi:10.1038/cdd.2017.151.

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