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 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-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-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-148a is 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.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (81772609, 81472549, 31521091) and National Key R&D Program of China (2016YFC1302300, 2014CB910600). We thank Professor Hongbing Shu (Wuhan University, Wuhan, China) for providing reagents and the Model Animal Research Center of Nanjing University for miR-148a KO mice.
Author contributions
YZ, LG, YL and YL designed the study, analyzed and interpreted the data and wrote the manuscript. YZ, LG and YL performed most of the experiments. BZ and EP provided the reagents. JZ, FZ and QZ provided the human colon samples. YL and EP wrote the manuscript.
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Zhu, Y., Gu, L., Li, Y. et al. miR-148a inhibits colitis and colitis-associated tumorigenesis in mice. Cell Death Differ 24, 2199–2209 (2017). https://doi.org/10.1038/cdd.2017.151
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DOI: https://doi.org/10.1038/cdd.2017.151
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