STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation

Yuet Mei Hazel Tye, Catherine Lydia Kennedy, Meri Najdovska, Louise McLeod, William McCormack, Norman R Hughes, Anouk Tara Dev, William Sievert, Chia Huey Ooi, T Ishikawa, Hiroko Oshima, Prithi S Bhathal, Andrew E Parker, Masanobu Oshima, Patrick Tan, Brendan John Jenkins

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167 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)466 - 478
Number of pages13
JournalCancer Cell
Volume22
Issue number4
DOIs
Publication statusPublished - 2012

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