Helicobacter pylori and the BMP pathway regulate CDX2 and SOX2 expression in gastric cells
Helicobacter pylori and the BMP pathway regulate CDX2 and SOX2 expression in gastric cells
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DOI：
10.1093/carcin/bgs233
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发表时间：
2012-10-01
期刊：
影响因子：
4.7
通讯作者：
Almeida, Raquel
中科院分区：
文献类型：
--
作者：
Camilo, Vania;Barros, Rita;Almeida, Raquel
幽门螺杆菌感染是肠上皮化生和胃癌发生的主要危险因素。IM是由转录因子CDX 2诱导的肿瘤前病变，其中胃粘膜转化为肠表型。我们以前证明了骨形态发生蛋白（BMP）通路的关键元件与IM中的CDX 2共定位，并上调胃细胞系中的CDX 2表达。这些观察结果，以及CDX 2可以被SOX 2抑制的假设，使我们测试H。pylori感染时，通过BMPs，SOX 2和CDX 2可以参与IM发展的关键分子网络。将SMAD 4敲低和未敲低的AGS细胞与H. pylori或BMP 2，以通过qPCR和蛋白质印迹评估BMP途径成员以及CDX 2和SOX 2的表达。还进行邻近连接测定（PLA）以评估SMAD蛋白相互作用。免疫组化和western blot检测幽门螺杆菌感染小鼠的胃组织。检测Smad 4、pSmad 1/5/8、Cdx 2和Sox 2在体内的表达。在与H. pylori或BMP 2。这些作用受到BMP通路下调的损害。最后，感染的小鼠呈现BMP通路上调、局部Cdx 2表达和Sox 2降低。这些结果提供了一个新的H。pylori感染和BMP途径在调节可能与胃IM相关的肠和胃特异性基因中的作用。
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.