MicroRNA Expression Profiling in the Histological Subtypes of Barrett's Metaplasia - PubMed (original) (raw)

Stefano Volinia, Jeff Palatini, Marco Pizzi, Cecilia Fernandez-Cymering, Mariangela Balistreri, Stefano Realdon, Giorgio Battaglia, Rhonda Souza, Robert D Odze, Giovanni Zaninotto, Carlo M Croce, Massimo Rugge Md Facg

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MicroRNA Expression Profiling in the Histological Subtypes of Barrett's Metaplasia

Matteo Fassan et al. Clin Transl Gastroenterol. 2013.

Abstract

Objectives: The histological definition of Barrett's esophagus (BE) is debated, particularly regarding the phenotype of its metaplastic columnar epithelium. Histologically proven intestinal metaplasia (IM) was the sine qua non condition for a diagnosis of BE but, more recently, non-intestinalized (i.e., cardiac gastric-type; GM) columnar metaplasia has been re-included in the spectrum of Barrett's histology. MicroRNAs modulate cell commitment, and are also reportedly dysregulated in Barrett's carcinogenesis. This study investigates miRNA expression in the histological spectrum of esophageal columnar metaplastic changes, specifically addressing the biological profile of GM vs. IM.

Methods: A study was performed to discover microRNA microarray in 30 matching mucosa samples obtained from 10 consecutive BE patients; for each patient, biopsy tissue samples were obtained from squamous, GM and intestinalized epithelium. Microarray findings were further validated by qRT-PCR analysis in another bioptic series of 75 mucosa samples.

Results: MicroRNA profiling consistently disclosed metaplasia-specific microRNA signatures. Six microRNAs were significantly dysregulated across the histological phenotypes considered; five of them (two overexpressed (hsa-miR-192; -miR-215) and three under-expressed (hsa-miR-18a*; -miR-203, and -miR-205)) were progressively dysregulated in the phenotypic sequence from squamous to gastric-type, to intestinal-type mucosa samples.

Conclusions: A consistent microRNA expression signature underlies both gastric- and intestinal-type esophageal metaplasia. The pattern of microRNA dysregulation suggests that GM may further progress to IM. The clinico-pathological implications of these molecular profiles prompt further study on the "personalized" cancer risk associated with each of these metaplastic transformations.

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Figures

Figure 1

Figure 1

miRNA expression is altered in esophageal metaplastic lesions. (a) miRNA significantly dysregulated (P<0.001) in gastric metaplasia (right panel) by comparison with squamous esophageal epithelium (left panel). (b) miRNA significantly dysregulated (P<0.001) in intestinal metaplasia (right panel) by comparison with squamous esophageal epithelium (left panel). Rows represent individual genes; columns represent individual tissue samples. The gray scale indicates transcript levels below, equal to, or above the mean (white, gray, and black, respectively); the scale represents the intensity of gene expression (log2 scale ranges between −3 and 3).

Figure 2

Figure 2

MicroRNA (miRNA) expression is altered in the progression from squamous epithelium to intestinal metaplasia. miRNA was significantly (FDR<0.001) dysregulated in the progression from squamous epithelium to gastric metaplasia to intestinal metaplasia. Rows represent individual genes; columns represent individual tissue samples. Pseudo-colors indicate transcript levels below, equal to, or above the mean (green, black, and red, respectively); the scale represents the intensity of gene expression (log2 scale ranges between −3 and 3).

Figure 3

Figure 3

qRT-PCR analysis for dysregulated miRNAs in metaplastic lesions. A total of 75 biopsy samples were considered, comprising: 15 squamous mucosa, 15 multilayered epithelium (MLE), 15 gastric metaplasia cardiac-type (GM), 15 low-density intestinal metaplasia (IM +/−), and 15 high-density IM. Two microRNAs (miRNAs; hsa-miR-192 and hsa-miR-215) were significantly upregulated in the metaplastic tissue by comparison with the squamous epithelium, whereas five miRNAs (hsa-miR-18a, hsa-miR-20a, hsa-miR-106a, hsa-miR-203, and hsa-miR-205) were downregulated. Rows represent individual genes; columns represent different lesion classes. Pseudo-colors indicate transcript levels below, equal to, or above the mean (green, black, and red, respectively); the scale represents the log2 difference between the mean expression levels seen in the metaplastic lesions and squamous epithelium. Numerical values are given in Table 3.

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