p53의 음성적 조절인자로써의 STAT3 타겟 유전자 FAT10에 대한 연구

Abstract

Inflammation is a host defense mechanism against pathogens. Following the production of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α, by recruited immune cells, cell death decreases and stem cells and epithelial cells proliferate. These changes facilitate wound healing and tissue regeneration. However, if the tight regulation of the inflammatory response fails, it causes a state of prolonged inflammation called chronic inflammation. Chronic inflammation is a primary cause of tumorigenesis, and studies of inflammatory bowel disease, colon cancer, Helicobacter pylori infection, gastritis and stomach cancer, HBV, HCV, and hepatocellular carcinoma indicated that inflammation is correlated with cancer progression. The molecular mechanism that links inflammation and cancer remains unclear, except for the activation of STAT3 and NFκB by the pro-inflammatory cytokines IL-6 and TNF-α, respectively. In addition, clinical trials of drugs that inhibit STAT3 and NFκB activation reported lower efficiency than expected. Further studies are needed to investigate the anti-cancer effects of STAT3 and NFκB and the regulatory mechanisms mediated by these molecules. In this study, microarray analysis about inflammation and cancer identified the candidate gene FAT10, which is related to inflammatory carcinogenesis. After stimulation with IL-6 and TNF-α, increased FAT10 levels repress the transcriptional activity of the tumor suppressor p53, a protein that accelerates the protein degradation of FAT10. This FAT10-p53 double-negative regulation is critical in the control of tumorigenesis, as overexpressed FAT10 facilitates tumor progression in a solid tumor model. In conclusion, transcriptional synergy between STAT3 and NFκB facilitates the role of FAT10 in the mutually inhibitory FAT10-p53 regulatory loop and favors tumorigenesis under inflammatory conditions.