The transcription factor MIST1 is a novel human gastric chief cell marker whose expression is lost in metaplasia, dysplasia, and carcinoma.

Abstract

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 TFF2 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 (TFF2(+)/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 (n > 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 ( approximately 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.

• Authors: Jochen K M Lennerz, Seok-Hyung Kim, Edward L Oates, Won Jae Huh, Jason M Doherty, Xiaolin Tian, Andrew J Bredemeyer, James R Goldenring, Gregory Y Lauwers, Young-Kee Shin, Jason C Mills
• Journal: The American journal of pathology (Am J Pathol) Vol. 177 Issue 3 Pg. 1514-33 (Sep 2010) ISSN: 1525-2191 [Electronic] United States
• PMID: 20709804 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Adaptor Proteins, Signal Transducing
• CLNK protein, human
• TFF2 protein, human
• Trefoil Factor-2

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Blotting, Western
• Cells, Cultured
• Chief Cells, Gastric (metabolism, pathology)
• Gastric Mucosa (metabolism, pathology)
• Gastrointestinal Diseases (genetics, metabolism, pathology)
• Gastrointestinal Tract (metabolism, pathology)
• Humans
• Immunohistochemistry
• Metaplasia (genetics, metabolism, pathology)
• Microscopy, Confocal
• Tissue Array Analysis
• Trefoil Factor-2