gp130-Mediated Stat3 Activation in Enterocytes Regulates Cell Survival and Cell-Cycle Progression during Colitis-Associated Tumorigenesis Academic Article uri icon

abstract

  • 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.

authors

  • Bollrath, Julia
  • Phesse, Toby J
  • von Burstin, Vivian A
  • Putoczki, Tracy
  • Bennecke, Moritz
  • Bateman, Trudie
  • Nebelsiek, Tim
  • Lundgren-May, Therese
  • Canli, Özge
  • Schwitalla, Sarah
  • Matthews, Vance
  • Schmid, Roland M
  • Kirchner, Thomas
  • Arkan, Melek C
  • Ernst, Matthias
  • Greten, Florian R

publication date

  • February 2009