gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis.
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.
Bollrath
Julia
J
2nd Department of Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
Phesse
Toby J
TJ
von Burstin
Vivian A
VA
Putoczki
Tracy
T
Bennecke
Moritz
M
Bateman
Trudie
T
Nebelsiek
Tim
T
Lundgren-May
Therese
T
Canli
Ozge
O
Schwitalla
Sarah
S
Matthews
Vance
V
Schmid
Roland M
RM
Kirchner
Thomas
T
Arkan
Melek C
MC
Ernst
Matthias
M
Greten
Florian R
FR
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology*; D003092:Colitis / Q000150:complications / Q000276:immunology / Q000473:pathology; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D020895:Enterocytes / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D017370:Interleukin-11 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000209:etiology / Q000276:immunology / Q000473:pathology; D012038:Regeneration / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D018797:Cell Cycle Proteins; D017370:Interleukin-11; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130