Helicobacter pylori and the BMP pathway regulate CDX2 and SOX2 expression in gastric cells.
Helicobacter pylori infection is the main risk factor for intestinal metaplasia (IM) and gastric cancer development. IM is a pre-neoplastic lesion, induced by the transcription factor CDX2, where the gastric mucosa is converted to an intestinal phenotype. We previously demonstrated that key elements of the bone morphogenetic protein (BMP) pathway co-localize with CDX2 in IM and upregulate CDX2 expression in gastric cell lines. These observations, together with the hypothesis that CDX2 could be repressed by SOX2, led us to test whether H. pylori, through BMPs, SOX2 and CDX2 could participate in a molecular network critical for the development of IM. AGS cells with and without SMAD4 knock-down were co-cultured with H. pylori or BMP2 to assess the expression of BMP pathway members as well as CDX2 and SOX2 by qPCR and western blot. Proximity ligation assay (PLA) was also performed to evaluate SMAD proteins interaction. Immunohistochemistry and western blot were performed in gastric samples from mice infected with Helicobacter spp. to measure Smad4, pSmad1/5/8, Cdx2 and Sox2 expression in vivo. Increased expression and activity of the BMP pathway accompanied by CDX2 upregulation and SOX2 downregulation were observed in AGS cells co-cultured with H. pylori or BMP2. These effects were impaired by downregulation of the BMP pathway. Finally, infected mice present BMP pathway upregulation, focal Cdx2 expression and decreased Sox2. These results provide a novel link between H. pylori infection and the BMP pathway in the regulation of intestinal and gastric-specific genes that might be relevant for gastric IM.
Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
Vânia
V
Camilo
Rita
R
Barros
Sofia
S
Sousa
Ana Maria
AM
Magalhães
Teresa
T
Lopes
António
A
Mário Santos
Teresa
T
Pereira
Céu
C
Figueiredo
Leonor
L
David
Raquel
R
Almeida
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D005753:Gastric Mucosa / Q000378:metabolism; D005786:Gene Expression Regulation; D016480:Helicobacter pylori / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D051785:Smad Proteins / Q000235:genetics; D013274:Stomach Neoplasms / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D000071616:CDX2 Transcription Factor; D018398:Homeodomain Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051785:Smad Proteins; D015534:Trans-Activators