A molecular signature of gastric metaplasia arising in response to acute parietal cell loss
A molecular signature of gastric metaplasia arising in response to acute parietal cell loss
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DOI：
10.1053/j.gastro.2007.11.058
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发表时间：
2008-02-01
期刊：
影响因子：
29.4
通讯作者：
Goldenring, James R.
中科院分区：
文献类型：
--
作者：
Nozaki, Koji;Ogawa, Masako;Goldenring, James R.
背景与目的：胃壁细胞的缺失是胃上皮化生和肿瘤形成的重要前体。然而，化生的起源仍然不清楚。急性壁细胞。在用GST-777处理的胃泌素缺陷小鼠中的损失导致从胃底腺基部快速出现痉挛多肽/三叶因子家族2（TFF 2）表达性化生（SPEM）。我们现在试图更明确地描述SPEM出现的途径。研究方法：在胃泌素缺陷小鼠中，用ESTA-777处理的新兴SPEM谱系进行了TFF 2、内在因子和Mist 1的免疫定位检查，并用电子显微镜进行形态学检查。新兴SPEM分离激光捕获显微切割和RNA进行了分析，使用基因微阵列。使用小鼠和人样品中的免疫组织化学来确认上调的转录物。结果如下：TFF 2、分化的主细胞标志物Mist 1和内因子均呈免疫反应性，提示SPEM来源于主细胞的转分化。微阵列分析的显微切割的SPEM谱系诱导的IFN-γ-777显示上调与G1/S细胞周期转换，包括微染色体维持缺陷蛋白，以及一些分泌因子，包括人附睾4（HE 4）的转录。HE 4在正常胃组织中不表达，但在人和小鼠的SPEM、人的肠上皮化生和胃癌组织中均有表达。结论：虽然传统上认为化生起源于正常的粘膜祖细胞，但这些研究表明，SPEM通过主细胞的转分化或基底隐蔽祖细胞的活化而进化。此外，化生的诱导还能促进分泌因子如HE 4的表达，这些因子与胃癌前病变有关。
Background & Aims: Loss of gastric parietal cells is a critical precursor to gastric metaplasia and neoplasia. However, the origin of metaplasia remains obscure. Acute parietal cell. loss in gastrin-deficient mice treated with DMP-777 leads to the rapid emergence of spasmolytic polypeptide/trefoil factor family 2 (TFF2)-expressing metaplasia (SPEM) from the bases of fundic glands. We now sought to characterize more definitively the pathway for emergence of SPEM. Methods: Emerging SPEM lineages in gastrin-deficient mice treated with DMP-777 were examined for immunolocalization of TFF2, intrinsic factor, and Mist1, and morphologically with electron microscopy. Emerging SPEM was isolated with laser-capture microdissection and RNA was analyzed using gene microarrays. Immunohistochemistry in mouse and human samples was used to confirm up-regulated transcripts. Results: DMP-777-induced SPEM was immunoreactive for TFF2 and the differentiated chief cell markers, Mist1 and intrinsic factor, suggesting that SPEM derived from transdifferentiation of chief cells. Microarray analysis of microdissected SPEM lineages induced by DMP-777 showed up-regnlation of transcripts associated with G1/S cell-cycle transition including minichromosome maintenance deficient proteins, as well as a number of secreted factors, including human epididymis 4 (HE4). HE4, which was absent in the normal stomach, was expressed in SPEM of human and mouse and in intestinal metaplasia and gastric cancer in human beings. Conclusions: Although traditionally metaplasia was thought to originate from normal mucosal progenitor cells, these studies indicate that SPEM evolves through either transdifferentiation of chief cells or activation of a basal cryptic progenitor. In addition, induction of metaplasia elicits the expression of secreted factors, such as HE4, relevant to gastric preneoplasia.