TITLE: The Roles of STAT3 and Its Targeting in Inflammation and Cancer

SPEAKER :  예 상 규 교수 (서울대학교 의과대학 약리학교실)

Education / Research Experiences

Public Research

STAT3-RANTES autocrine signaling is essential for tamoxifen resistance in human breast cancer cells, Mol Cancer Res,(2013) 외 90여편

ABSTRACT

Our previous study has clearly shown that STAT3 up-regulates iNOS, COX-2 expression in brain inflammation, and modulates hypoxia inducible factor 1α (HIF-1α) protein stability and enhances HIF-1-mediated expression of VEGF in hypoxic solid tumors.

In inflammation, LPS or a viral components (double-stranded (ds)RNA) lead to a STAT3-dependent inflammatory response that induces pro-inflammatory mediators in brain microglia. Based on our results, we evaluate underling mechanism of anti-inflammatory effect of ethyl pyruvate (EP) on microglia activation in brain. EP significantly suppressed the LPS-induced microglia activation, accompanied by inhibiting STAT3 in vivo and in vitro.

In tumor, caffeic acid (CA) and its derivative, 3-(3, 4-Dihydroxy-phenyl)-acrylic acid 2-(3, 4-dihydroxy-phenyl)-ethyl ester (CADPE) can exert their anticancer activity by targeting STAT3 using in vitro and in vivo system. In addition, 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) as a small molecule inhibitor of STAT3 signaling was more potent in JAK3-activated Hodgkin’s lymphoma L540 cells.

In addition, a mouse model of ulcerative colitis was developed to investigate the linkage of IL-6 and S100a9 in IECs. We found that the elevated S100a9 expression mediated by IL-6/STAT3 in CECs plays an important role in the manifestation of ulcerative colitis. We also found that Simvastatin suppressed RANTES-induced neutrophilia via STAT3 inactivation in poly I:C-induced pneumonia model. These findings suggest that simvastatin may be a potential drug candidate for the treatment of viral pneumonia. Moreover, we demonstrate that CD133 up-regulation requires STAT3 phosphorylation, showing that CD133 expression is directly regulated by STAT3 upon IL-6 and IL-23 stimulations in HCC cells. We finally found that STAT3 inhibitors will give new strategies to prevent developing acquired resistance or to manage Tamoxifen resistance breast cancer cells. Consequently, our research will ultimately lead to the development of better molecular markers for inflammation and cancer development and better drugs for treatment of inflammatory diseases and tumors.