title: SOX9 Elevation Acts with Canonical WNT Signaling to Drive Gastric Cancer Progression.
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 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 gastric cancer 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 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 β-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. Cancer Res; 76(22); 6735-46. ©2016 AACR.
authors: Unidade Integrada de Farmacologia e Gastroenterologia, Universidade São Francisco, Bragança Paulista, São Paulo, Brazil.|Programa de Pos Graduação em Genetica e Biologia Molecular, State University of Campinas, Campinas, São Paulo, Brazil.
authors: Juliana Carvalho
authors: JC
authors: Santos
authors: Neuro-oncology group, Biodonostia Health Research Institute, San Sebastian, Spain.
authors: Estefania
authors: E
authors: Carrasco-Garcia
authors: Neuro-oncology group, Biodonostia Health Research Institute, San Sebastian, Spain.
authors: Mikel
authors: M
authors: Garcia-Puga
authors: Neuro-oncology group, Biodonostia Health Research Institute, San Sebastian, Spain.
authors: Paula
authors: P
authors: Aldaz
authors: Microbiology Service, Biodonostia Health Research Institute and Hospital Donostia, San Sebastian, Spain.
authors: Milagrosa
authors: M
authors: Montes
authors: Microbiology Service, Biodonostia Health Research Institute and Hospital Donostia, San Sebastian, Spain.
authors: Maria
authors: M
authors: Fernandez-Reyes
authors: Unidade Integrada de Farmacologia e Gastroenterologia, Universidade São Francisco, Bragança Paulista, São Paulo, Brazil.
authors: Caroline Candida
authors: CC
authors: de Oliveira
authors: IKERBASQUE Basque Foundation for Science, Bilbao, Spain.|Molecular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain.
authors: Charles H
authors: CH
authors: Lawrie
authors: IKERBASQUE Basque Foundation for Science, Bilbao, Spain.|Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, San Sebastian, Spain.
authors: Marcos J
authors: MJ
authors: Araúzo-Bravo
authors: Unidade Integrada de Farmacologia e Gastroenterologia, Universidade São Francisco, Bragança Paulista, São Paulo, Brazil. ander.matheu@biodonostia.org marcelo.ribeiro@usf.edu.br.|Programa de Pos Graduação em Genetica e Biologia Molecular, State University of Campinas, Campinas, São Paulo, Brazil.
authors: Marcelo Lima
authors: ML
authors: Ribeiro
authors: Neuro-oncology group, Biodonostia Health Research Institute, San Sebastian, Spain. ander.matheu@biodonostia.org marcelo.ribeiro@usf.edu.br.|IKERBASQUE Basque Foundation for Science, Bilbao, Spain.
authors: Ander
authors: A
authors: Matheu
mesh_terms: D000818:Animals; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D055758:SOX9 Transcription Factor / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human