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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

SOX9 Elevation Acts with Canonical WNT Signaling to Drive Gastric Cancer Progression

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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, Ander
Total Authors: 11
Document type: Journal article
Source: Cancer Research; v. 76, n. 22, p. 6735-6746, NOV 15 2016.
Web of Science Citations: 31
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. (AU)

FAPESP's process: 14/11862-6 - Evaluation of the regulatory role of genes associated with the via Wnt/b-catenin on the mechanisms of the DNA repair modulated by H. pylori
Grantee:Marcelo Lima Ribeiro
Support type: Regular Research Grants