STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation.
Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium. Increased STAT3 pathway activation and TLR2 expression were also associated with poor GC patient survival. Collectively, our data reveal an unexpected role for TLR2 in the oncogenic function of STAT3 that may represent a therapeutic target in GC.
Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia.
Hazel
H
Tye
Catherine L
CL
Kennedy
Meri
M
Najdovska
Louise
L
McLeod
William
W
McCormack
Norman
N
Hughes
Anouk
A
Dev
William
W
Sievert
Chia Huey
CH
Ooi
Tomo-o
TO
Ishikawa
Hiroko
H
Oshima
Prithi S
PS
Bhathal
Andrew E
AE
Parker
Masanobu
M
Oshima
Patrick
P
Tan
Brendan J
BJ
Jenkins
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D050822:Cytokine Receptor gp130 / Q000502:physiology; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050796:STAT3 Transcription Factor / Q000502:physiology*; D013274:Stomach Neoplasms / Q000209:etiology*; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D015854:Up-Regulation
C494200:Il6st protein, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D050822:Cytokine Receptor gp130