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Type: Artigo
Title: Sox9 Elevation Acts With Canonical Wnt Signaling To Drive Gastric Cancer Progression
Author: Santos
Juliana Carvalho; Carrasco-Garcia
Estefania; Garcia-Puga
Mikel; Aldaz
Paula; Montes
Milagrosa; Fernandez-Reyes
Maria; de Oliveira
Caroline Candida; Lawrie
Charles H.; Arauzo-Bravo
Marcos J.; Ribeiro
Marcelo Lima; Matheu
Abstract: Gastric cancer remains one of the leading causes of global cancer mortality due to therapy resistance, with Helicobacter pylori (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 TNF alpha. 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 gastric cancer cell proliferation, increased levels of beta-catenin, and acquisition of stem cell-like properties. Analysis of three large clinical cohorts revealed elevated SOX9 levels in gastric cancer with advanced tumor stage and poor patient survival. Functionally, SOX9 silencing in gastric cancer 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 b-catenin expression suggested the existence of 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.
Editor: Amer Assoc Cancer Research
Rights: fechado
Identifier DOI: 10.1158/0008-5472.CAN-16-1120
Date Issue: 2016
Appears in Collections:Unicamp - Artigos e Outros Documentos

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