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


ABSTRACT: 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 ?B (NF-?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 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 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-?B and STAT3 signaling, including GP130, IKK?, IKK?, IL1R1 and TNFR2, which leads to decreased NF-?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-?B and STAT3 and their pro-inflammatory consequences.

SUBMITTER: Zhu Y 

PROVIDER: S-EPMC5686357 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Zhu Yahui Y   Gu Li L   Li Yajun Y   Lin Xi X   Shen Hongxing H   Cui Kaisa K   Chen Li L   Zhou Feng F   Zhao Qiu Q   Zhang Jinxiang J   Zhong Bo B   Prochownik Edward E   Li Youjun Y  

Cell death and differentiation 20170929 12


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 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 c  ...[more]

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