[PDF][PDF] gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis

J Bollrath, TJ Phesse, VA von Burstin, T Putoczki… - Cancer cell, 2009 - cell.com
J Bollrath, TJ Phesse, VA von Burstin, T Putoczki, M Bennecke, T Bateman, T Nebelsiek…
Cancer cell, 2009cell.com
Although gastrointestinal cancers are frequently associated with chronic inflammation, the
underlying molecular links have not been comprehensively deciphered. Using loss-and gain-
of-function mice in a colitis-associated cancer model, we establish here a link comprising the
gp130/Stat3 transcription factor signaling axis. Mutagen-induced tumor growth and
multiplicity are reduced following intestinal epithelial cell (IEC)-specific Stat3 ablation, while
its hyperactivation promotes tumor incidence and growth. Conversely, IEC-specific Stat3 …
Summary
Although gastrointestinal cancers are frequently associated with chronic inflammation, the underlying molecular links have not been comprehensively deciphered. Using loss- and gain-of-function mice in a colitis-associated cancer model, we establish here a link comprising the gp130/Stat3 transcription factor signaling axis. Mutagen-induced tumor growth and multiplicity are reduced following intestinal epithelial cell (IEC)-specific Stat3 ablation, while its hyperactivation promotes tumor incidence and growth. Conversely, IEC-specific Stat3 deficiency enhances susceptibility to chemically induced epithelial damage and subsequent mucosal inflammation, while excessive Stat3 activation confers resistance to colitis. Stat3 has the capacity to mediate IL-6- and IL-11-dependent IEC survival and to promote proliferation through G1 and G2/M cell-cycle progression as the common tumor cell-autonomous mechanism that bridges chronic inflammation to tumor promotion.
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