SOX9 and gastric cancer

Gastric cancer (GC) remains one of the leading causes of global cancer mortality due to therapy resistance, with H. pylori infection being a major risk factor. In this study, we report the significance of an elevation of the stem cell regulator SOX9 in bacteria-infected human gastritis and cancer samples, paralleling increased levels of TNFα. SOX9 elevation was more intense in specimens containing the pathogenically significant cagA+ strains of H. pylori. Notably, we found that SOX9 was required for bacteria-induced GC cell proliferation, increased levels of β-catenin and acquisition of stem cell-like properties. Analysis of three large clinical cohorts revealed elevated SOX9 levels in GC with advanced tumor stage and poor patient survival. Functionally, SOX9 silencing in GC cells enhanced apoptosis and senescence, concomitantly with a blockade to self-renewal and tumor initiating capability. Paralleling these effects, we also found SOX9 to mediate cisplatin chemoresistance associated with reduced disease-free survival. Mechanistic interactions between SOX9 and β-catenin expression suggested the existence a regulatory role for SOX9 targeting the WNT canonical pathway. Taken together, our findings establish the significance of SOX9 in gastric cancer pathobiology and heterogeneity, with implications for targeting WNT-SOX9 signaling as a rational therapeutic strategy.

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