The Transcription Factor MIST1 Is a Novel Human Gastric Chief Cell Marker Whose Expression Is Lost in Metaplasia, Dysplasia, and Carcinoma
The Transcription Factor MIST1 Is a Novel Human Gastric Chief Cell Marker Whose Expression Is Lost in Metaplasia, Dysplasia, and Carcinoma
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DOI：
10.2353/ajpath.2010.100328
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发表时间：
2010-09-01
影响因子：
6
通讯作者：
Mills, Jason C.
中科院分区：
文献类型：
--
作者：
Lennerz, Jochen K. M.;Kim, Seok-Hyung;Mills, Jason C.
由于缺乏可靠的正常分化上皮细胞的分子标记物，限制了对人类胃癌发生的理解。公认的胃腺癌前病变是肠上皮化生和痉挛性多肽表达化生（SPEM），在此分别定义为异位CDX 2和TFE 2表达。在小鼠中，通常限于成熟主细胞的bHLH转录因子MIST 1的表达随着主细胞经历实验诱导的化生而下调。在这里，我们表明MIST 1表达也是人类主细胞的特异性标志物。有和没有MIST 1的SPEM存在于人类病变中，并且类似于鼠数据，可能代表过渡期（TFF 2（+）/MIST 1（+）=“杂交”-SPEM）和确定期（TIT 2（+）/MIST 1（-）= SPEM）。MIST 1和CDX 2的共同可视化显示了类似的MIST 1进行性丢失，具有过渡性CDX 2（+）/MIST 1（-）混合肠化生阶段。组织微阵列、切除标本和活检结果的机构间分析和比较（> 400个样品），包括公认的胃癌发生阶段的整个谱，证实了MIST 1表达限于正常泌酸粘膜中的主细胞区室，在已建立的化生性病变中罕见，在上皮内瘤变/异型增生和各种类型的癌中丢失，除了罕见的主细胞癌（类似于1%）。我们的研究结果暗示MIST 1是成熟、健康主细胞的可靠标志物，我们提供了人类化生至少部分来自主细胞谱系的第一个证据。(Am J Pathol 2010，177-1514-1533; DOI：10.2353/ajpath.2010.100328）
The lack of reliable molecular markers for normal differentiated epithelial cells limits understanding of human gastric carcinogenesis. Recognized precursor lesions for gastric adenocarcinoma are intestinal metaplasia and spasmolytic polypeptide expressing metaplasia (SPEM), defined here by ectopic CDX2 and TFE2 expression, respectively. In mice, expression of the bHLH transcription factor MIST1, normally restricted to mature chief cells, is down-regulated as chief cells undergo experimentally induced metaplasia. Here, we show MIST1 expression is also a specific marker of human chief cells. SPEM, with and without MIST1, is present in human lesions and, akin to murine data, likely represents transitional (TFF2(+)/MIST1(+) = "hybrid"-SPEM) and established (TIT2(+)/ MIST1(-) = SPEM) stages. Co-visualization of MIST1 and CDX2 shows similar progressive loss of MIST1 with a transitional, CDX2(+)/MIST1(-) hybrid-intestinal metaplasia stage. Interinstitutional analysis and comparison of findings in tissue microarrays, resection specimens, and biopsies (is > 400 samples), comprising the entire spectrum of recognized stages of gastric carcinogenesis, confirm MIST1 expression is restricted to the chief cell compartment in normal oxyntic mucosa, rare in established metaplastic lesions, and lost in intraepithelial neoplasia/dysplasia and carcinoma of various types with the exception of rare chief cell carcinoma (similar to 1%). Our findings implicate MIST1 as a reliable marker of mature, healthy chief cells, and we provide the first evidence that metaplasia in humans arises at least in part from the chief cell lineage. (Am J Pathol 2010, 177-1514-1533; DOI: 10.2353/ajpath.2010.100328)