Heterogeneity in mouse spasmolytic polypeptide-expressing metaplasia lineages identifies markers of metaplastic progression.

Abstract

OBJECTIVES:

Spasmolytic polypeptide-expressing metaplasia (SPEM) develops as a preneoplastic lesion in the stomachs of mice and humans after parietal cell loss. To identify the commonalities and differences between phenotypic SPEM lineages, SPEM were studied from three different mouse models of parietal cell loss: with chronic inflammation with Helicobacter felis infection; with acute inflammation with L635 treatment; and without inflammation following DMP-777 treatment.

DESIGN:

RNA transcripts from laser capture microdissected normal chief cells and SPEM lineages were compared using gene microarray. Alterations in transcripts were validated by quantitative real-time PCR. Clusterin and cystic fibrosis transmembrane conductance regulator (CFTR) were selected for immunohistochemical analysis in all mouse models as well as in human SPEM, intestinal metaplasia and gastric cancer.

RESULTS:

Transcript expression patterns demonstrated differences among the phenotypic SPEM models. Clusterin expression was significantly upregulated in all three mouse SPEM models as well as in human SPEM. The highest clusterin expression in human gastric cancers correlated with poor survival. Conversely, CFTR expression was upregulated only in SPEM with inflammation in mice. In humans, intestinal metaplasia, but not SPEM, expressed CFTR.

CONCLUSIONS:

While markers such as clusterin are expressed in all phenotypic SPEM lineages, distinct patterns of upregulated genes including CFTR are present in murine metaplasia associated with inflammation, indicative of progression of metaplasia towards a more intestinalised metaplastic phenotype.

• Authors: Victoria G Weis, Josane F Sousa, Bonnie J LaFleur, Ki Taek Nam, Jared A Weis, Paul E Finke, Nadia A Ameen, James G Fox, James R Goldenring
• Journal: Gut (Gut) Vol. 62 Issue 9 Pg. 1270-9 (Sep 2013) ISSN: 1468-3288 [Electronic] England
• PMID: 22773549 (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

• Azetidines
• Biomarkers
• Clusterin
• Intercellular Signaling Peptides and Proteins
• Peptides
• Piperazines
• spasmolytic polypeptide
• Cystic Fibrosis Transmembrane Conductance Regulator
• DMP 777

Topics

• Animals
• Azetidines (pharmacology)
• Biomarkers (metabolism)
• Clusterin (metabolism)
• Cystic Fibrosis Transmembrane Conductance Regulator (metabolism)
• Disease Models, Animal
• Gene Expression Profiling
• Gene Expression Regulation
• Helicobacter Infections (complications)
• Humans
• Inflammation (drug therapy, etiology, genetics, metabolism)
• Intercellular Signaling Peptides and Proteins
• Intestines (pathology)
• Laser Capture Microdissection
• Metaplasia (diagnosis, etiology, genetics, metabolism)
• Mice
• Mice, Inbred CFTR
• Parietal Cells, Gastric (metabolism, pathology)
• Peptides (genetics, metabolism)
• Piperazines (pharmacology)
• Precancerous Conditions (genetics, metabolism)
• Up-Regulation