MSH2 Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer Development.

Cancer Res 2016 08 3;76(15):4383-93. Epub 2016 Jun 3.

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Inflammation predisposes to tumorigenesis in various organs by potentiating a susceptibility to genetic aberrations. The mechanism underlying the enhanced genetic instability through chronic inflammation, however, is not clear. Here, we demonstrated that TNFα stimulation induced transcriptional downregulation of MSH2, a member of the mismatch repair family, via NF-κB-dependent miR-21 expression in hepatocytes. Liver cancers developed in ALB-MSH2(-) (/) (-)AID(+), ALB-MSH2(-) (/) (-), and ALB-AID(+) mice, in which MSH2 is deficient and/or activation-induced cytidine deaminase (AICDA) is expressed in cells with albumin-producing hepatocytes. The mutation signatures in the tumors developed in these models, especially ALB-MSH2(-) (/) (-)AID(+) mice, closely resembled those of human hepatocellular carcinoma. Our findings demonstrated that inflammation-mediated dysregulation of MSH2 may be a mechanism of genetic alterations during hepatocarcinogenesis. Cancer Res; 76(15); 4383-93. ©2016 AACR.

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http://dx.doi.org/10.1158/0008-5472.CAN-15-2926DOI Listing
August 2016
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