title: CDX2 can be regulated through the signalling pathways activated by IL-6 in gastric cells.
abstract: The inflammatory infiltrate of the gastric mucosa associated with Helicobacter pylori infection increases the presence of the pro-inflammatory cytokine IL-6 that activates both the SHP-2/ERK/MAPK and the JAK/STAT signalling pathways. Furthermore, the ectopic expression of CDX2 is detected in pre-neoplasic lesions associated with decreased levels of SOX2, and we found that in gastric adenocarcinomas their expression is inversely correlated. To determine the role of IL-6 in the regulation of CDX2, MKN45 that constitutively expresses p-STAT3, and NUGC-4 gastric cancer cell lines were treated with IL-6, which induced the CDX2 up-regulation and SOX2 down-regulation. ChIP assays determined that in IL-6-treated cells, c-JUN and p-STAT3 bound to CDX2 promoter in MKN45 cells whereas in NUGC-4 cells, p-STAT3 binds to and c-JUN releases from the CDX2 promoter. Specific inhibition of STAT3 and ERK1/2 phosphorylation through AG490 and U0126, respectively, and STAT3 down-regulation using shRNA verified that the SHP-2/ERK/MAPK pathway regulates the expression of CDX2 in basal conditions, and the CDX2 up-regulation by IL-6 is through the JAK/STAT pathway in NUGC-4 cells whereas in MKN45 cells both pathways contribute to the CDX2 up-regulation. In conclusion, the signalling pathways activated by IL-6 have a crucial role in the regulation of CDX2 that is a key factor in the process of gastric carcinogenesis, suggesting that the inflammatory infiltrate in the gastric mucosa is relevant in this process and a potential target for new therapeutic approaches.
authors: Gastroesophageal Cancer Research Group, Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors: Lara
authors: L
authors: Cobler
authors: Gastroesophageal Cancer Research Group, Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors: Manuel
authors: M
authors: Pera
authors: Gastroesophageal Cancer Research Group, Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors: Marta
authors: M
authors: Garrido
authors: Gastroesophageal Cancer Research Group, Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors: Mar
authors: M
authors: Iglesias
authors: Gastroesophageal Cancer Research Group, Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Dr. Aiguader, 88, 08003 Barcelona, Spain. Electronic address: cbolos@imim.es.
authors: Carme
authors: C
authors: de Bolós
mesh_terms: D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D016755:Proto-Oncogene Proteins c-jun; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: CDX2; Gastric preneoplasic lesion; Interleukin-6; c-JUN; p-STAT3