STAT3-Driven Upregulation of TLR2 Promotes Gastric Tumorigenesis Independent of Tumor Inflammation

SummaryGastric 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.

► STAT3 directly upregulates TLR2 expression in gastric epithelial cells and tumors ► Genetic and therapeutic blockade of TLR2 suppresses gastric tumorigenesis ► Protumorigenic TLR2 promotes gastric epithelial cell proliferation and survival ► High STAT3 activation and TLR2 expression correlate with poor GC patient survival