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Mol Cancer Res. 2011 Dec;9(12):1718-31. doi: 10.1158/1541-7786.MCR-10-0210. Epub 2011 Oct 12.

Cytokine induction of tumor necrosis factor receptor 2 is mediated by STAT3 in colon cancer cells.

Author information

1
Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.

Abstract

The IL-6/STAT3 and TNFα/NFκB pathways are emerging as critical mediators of inflammation-associated colon cancer. TNF receptor (TNFR) 2 expression is increased in inflammatory bowel diseases, the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated cancer, and by combined interleukin (IL) 6 and TNFα. The molecular mechanisms that regulate TNFR2 remain undefined. This study used colon cancer cell lines to test the hypothesis that IL-6 and TNFα induce TNFR2 via STAT3 and/or NFκB. Basal and IL-6 + TNFα-induced TNFR2 were decreased by pharmacologic STAT3 inhibition. NFκB inhibition had little effect on IL-6 + TNFα-induced TNFR2, but did inhibit induction of endogenous IL-6 and TNFR2 in cells treated with TNFα alone. Chromatin immunoprecipitation (ChIP) revealed cooperative effects of IL-6 + TNFα to induce STAT3 binding to a -1,578 STAT response element in the TNFR2 promoter but no effect on NFκB binding to consensus sites. Constitutively active STAT3 was sufficient to induce TNFR2 expression. Overexpression of SOCS3, a cytokine-inducible STAT3 inhibitor, which reduces tumorigenesis in preclinical models of colitis-associated cancer, decreased cytokine-induced TNFR2 expression and STAT3 binding to the -1,578 STAT response element. SOCS3 overexpression also decreased proliferation of colon cancer cells and dramatically decreased anchorage-independent growth of colon cancer cells, even cells overexpressing TNFR2. Collectively, these studies show that IL-6- and TNFα-induced TNFR2 expression in colon cancer cells is mediated primarily by STAT3 and provide evidence that TNFR2 may contribute to the tumor-promoting roles of STAT3.

PMID:
21994466
PMCID:
PMC3243771
DOI:
10.1158/1541-7786.MCR-10-0210
[Indexed for MEDLINE]
Free PMC Article

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