Inhibition of nuclear factor-κB signaling suppresses Spint1-deletion-induced tumor susceptibility in the ApcMin/+ model
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Makiko Kawaguchi1, Koji Yamamoto1, Ai Kanemaru1, Hiroyuki Tanaka1, Kazuo Umezawa2, Tsuyoshi Fukushima1, Hiroaki Kataoka1
1Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
2Department of Molecular Target Medicine Screening, Aichi Medical University School of Medicine, Aichi, Japan
Hiroaki Kataoka, email: firstname.lastname@example.org
Keywords: HAI-1, Spint1, DHMEQ, NF-κB, colon cancer
Received: April 12, 2016 Accepted: August 24, 2016 Published: September 06, 2016
Hepatocyte growth factor activator inhibitor type 1 (HAI-1), encoded by the Spint1 gene, is a membrane-bound serine protease inhibitor expressed on the epithelial cell surface. We have previously reported that the intestine-specific Spint1-deleted ApcMin/+ mice showed accelerated formation of intestinal tumors. In this study, we focused on the role of nuclear factor-κB (NF-κB) signaling in the HAI-1 loss-induced tumor susceptibility. In the HAI-1-deficient intestine, inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, were upregulated in normal mucosa. Furthermore, increased nuclear translocation of NF-κB was observed in both normal mucosa and tumor tissues of HAI-1-deficient ApcMin/+ intestines, and an NF-κB target gene, such as urokinase-type plasminogen activator, was upregulated in the HAI-1-deficient tumor tissues. Thus, we investigated the effect of dehydroxymethylepoxyquinomicin (DHMEQ), a synthetic inhibitor of NF-κB, on intestinal HAI-1-deficient ApcMin/+ mice. Treatment with DHMEQ reduced the formation of intestinal tumors compared with vehicle control in the HAI-1-deficient ApcMin/+ mice. These results suggested that insufficient HAI-1 function promotes intestinal carcinogenesis by activating NF-κB signaling.
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