miR-148a inhibits colitis and colitis-associated tumorigenesis in mice
miR-148a inhibits colitis and colitis-associated tumorigenesis in mice
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miR-148a 抑制小鼠结肠炎和结肠炎相关肿瘤的发生。
DOI：
10.1038/cdd.2017.151
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发表时间：
2017-12-01
影响因子：
12.4
通讯作者：
Zhao, Qiu
中科院分区：
文献类型：
--
作者：
Zhu, Yahui;Gu, Li;Zhao, Qiu
miR-148 a已被证明可调节炎症、免疫和某些肿瘤的生长，但其在结肠炎和结直肠肿瘤发生中的作用在很大程度上仍未确定。在这里，我们发现miR-148 a缺陷小鼠更容易患结肠炎和结肠炎相关的肿瘤发生。两者均与核因子κ B（NF-κ B B）和信号转导和转录激活因子3（STAT 3）信号传导增加相关。骨髓和非骨髓来源的miR-148 a促进结肠炎和结肠炎相关肿瘤发生。miR-148 a杂合性缺失加剧了Apc（min/+）结肠和小肠自发性肿瘤的发展。恢复miR-148 a表达可以预防自发性和致癌物诱导的结肠肿瘤发展。miR-148 a在人类炎症性肠病（IBD）和结直肠癌患者组织中下调。这与由P65和DNA甲基转移酶3 α（DNMT 3A）组成的复合物介导的miR-148 a启动子高度甲基化相关。miR-148 a直接靶向NF-κ B和STAT 3信号传导的几种公认的上游调节剂，包括GP 130、IKK α、IKK β、IL 1 R1和TNFR 2，这导致巨噬细胞和结肠组织中NF-κ B和STAT 3活化降低。我们的研究结果表明，miR-148 a是一种间接的肿瘤抑制因子，通过抑制NF-κ B B和STAT 3信号的表达及其促炎作用来调节结肠炎和结肠炎相关肿瘤的发生。
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.