Generation of intestinal metaplasia by ectopic expression of Cdx1 and Cdx2

Cdx1 和 Cdx2 异位表达产生肠上皮化生

• 批准号: 13470122
• 负责人: SUGANO Kentaro
• 金额: $ 9.02万
• 依托单位: Jichi Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470122/
• 关键词: intestinal metaplasia; transgenic mice; transcription factor; CDX1; CDX2; CDX

In an attempt to elucidate the mechanism of transdifferentiation of gastric and esophageal mucosa to intestinal metaplasia that is considered to be a precancerous state, we have generated mice models expressing either Cdx-1 or Cdx-2 homeobox gene in the parietal cells. In the Cdx-lexpressing mice, gastric fundic mucosa was gradually converted to intestinal mucosa with absorptive, goblet, entero-endocrine and Paneth cell lineage. By contrast, intestinal metaplasia developed by Cdx-2 expression in the gastric mucosa exhibit absorptive, goblet and entero-endocrine cells but lacked Paneth cell lineage. The intestinal metaplasia of these two mice models differs in terms of mucosal architecture. The regular and orderly architecture of intestinal pit to villus was lost and Paneth cells were dispersed in the tip portion of the villi in the Cdx-1 transgenic mice. In Cdx-2 mice, the psuedopyloric gland like portion was found in the base of the gland similar to the incomplete intestinal metaplasia. In both mice models, mucosal proliferation was accelerated resulting in hyperplasia and polyp-like formation was noted at the later stage. We are currently analyzing the alteration of the gene expression induced by the ectopic expression of Cdx-1 and Cdx-2. In human gastric and esophageal mucosa, we have confirmed that Cdx-2 expression precedes the phenotypic change to intestinal metaplasia, implicating its role as a trigger.

为了阐明胃和食管粘膜转分化为肠上皮化生（被认为是癌前状态）的机制，我们建立了在壁细胞中表达Cdx-1或Cdx-2同源框基因的小鼠模型。Cdx受体表达小鼠胃底粘膜逐渐向肠粘膜转化，具有吸收性、杯状、肠内分泌和潘氏细胞系。与此相反，在胃粘膜中由Cdx-2表达发展的肠上皮化生表现出吸收细胞、杯状细胞和肠内分泌细胞，但缺乏潘氏细胞谱系。这两种小鼠模型的肠上皮化生在粘膜结构方面不同。Cdx-1转基因小鼠小肠小凹到绒毛的结构失去了规律性和有序性，潘氏细胞分散在绒毛的顶端部分。在Cdx-2小鼠中，在腺体的基部发现假幽门腺样部分，类似于不完全肠化生。在两种小鼠模型中，粘膜增殖加速，导致增生，并在后期观察到息肉样形成。我们目前正在分析Cdx-1和Cdx-2的异位表达诱导的基因表达的改变。在人胃和食管粘膜中，我们已经证实Cdx-2表达先于肠上皮化生的表型变化，暗示其作为触发器的作用。

项目成果

H.Mutoh, K.Sugano et al.: "Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice"Biochem.Biophy.Res.Commun.. 294. 470-479 (2002)

H.Mutoh、K.Sugano 等：“表达 Cdx2 的转基因小鼠中胃粘膜向肠化生的转化”Biochem.Biophy.Res.Commun. 294. 470-479 (2002)

A.Eda, K.Sugano et al.: "Aberrant expression of CDX2 in Barrett's epithelium and inflammatory esophageal mucosa"J.Gastroenterology. 38. 14-22 (2003)

A.Eda、K.Sugano 等人：“Barrett 上皮和炎症性食管粘膜中 CDX2 的异常表达”J.Gastroenterology。

A.Eda, H.Osawa, K.Sugano: "Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia"J.Gastroenterology. 37・2. 94-100 (2002)

A.Eda、H.Osawa、K.Sugano：“在肠上皮化生的进展过程中同源框基因 CDX2 的表达先于 CDX1”J.Gastroenterology 37・2（2002）。

Kentaro Sugano: "Grading gastritis ; an impossible dream?"Gastric Cancer. 5. 58-60 (2002)

菅野健太郎：“胃炎分级；一个不可能实现的梦想？”胃癌。

Akashi Eda, Hiroyuki Osawa, Ichiro Yanaka, Kiichi Satoh, Hiroyuki Mutoh, Ken Kihira, Kentaro Sugano: "Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia"J.Gastroenterology. 37. 94-100 (2002)

Akashi Eda、Hiroyuki Osawa、Ichiro Yanaka、Kiichi Satoh、Hiroyuki Mutoh、Ken Kihira、Kentaro Sugano：“在肠化生进展过程中，同源框基因 CDX2 的表达先于 CDX1 的表达”J.Gastroenterology。