Abstract 3658: 90K attenuates the development of colitis-associated colorectal tumors through negative regulation of intestinal epithelial Toll-like receptor 4

Abstract

Abstract Background: Inflammation is a risk factor for colon cancer. TLR4 expression is upregulated in almost all colitis-associated cancer and dysplasia. The molecular mechanisms linking inflammation and colon carcinogenesis are incompletely understood. We found that tumor associated antigen 90K antagonized TLR4/NF-kB signaling pathway in colon cancer cells. We hypothesized that 90K is involved in TLR4 expression in colitis-induced colon carcinogenesis. Methods: The effect of 90K against TLR4 was analysed by cell cultures, NF-kB reporter assay, and immunoprecipitation. C57BL/6 mice were treated with 3% dextran sodium sulfate (DSS) for acute colitis model. Colitis was assessed by disease activity index (DAI) including weight loss, stool consistency and rectal bleeding, and histopathology. Results: 90K interacts with TLR4, suppresses the NF-kB signal in the MYD88-dependent pathway that is major adaptor molecules in TLRs/NF-kB signal. Adenoviral 90K administration attenuated the severity of acute DSS-induced colitis as assessed by DAI and histopathologic scoring compared with the control group. 90K restored body weight loss and the severity of acute DSS colitis through the suppression of TLR4/MYD88/NF-kB signal. Conclusions: Tumor associated antigen 90K is involved in negative regulation of inflammatory signaling triggered by TLR4-induced NF-kB activation. The data suggest that 90K might thereby suppress proliferation and progression of colon cancers. Citation Format: Ik-Joo Chung, Jun-Eul Hwang, Ji-Hee Lee. 90K attenuates the development of colitis-associated colorectal tumors through negative regulation of intestinal epithelial Toll-like receptor 4. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3658. doi:10.1158/1538-7445.AM2014-3658