Progression of Barrett's Metaplasia to Adenocarcinoma Is Associated with the Suppression of the Transcriptional Programs of Epidermal Differentiation

Abstract

We did expressional profiling on 24 paired samples of normal esophageal epithelium, Barrett's metaplasia, and esophageal adenocarcinomas. Matching tissue samples representing the three different histologic types were obtained from each patient undergoing esophagectomy for adenocarcinoma. Our analysis compared the molecular changes accompanying the transformation of normal squamous epithelium with Barrett's esophagus and adenocarcinoma in individual patients rather than in a random cohort. We tested the hypothesis that expressional profiling may reveal gene sets that can be used as molecular markers of progression from normal esophageal epithelium to Barrett's esophagus and adenocarcinoma. Expressional profiling was done using U133A GeneChip (Affymetrix), which represent approximately two thirds of the human genome. The final selection of 214 genes permitted the discrimination of differential gene expression of normal esophageal squamous epithelium, Barrett's esophagus, and adenocarcinoma using two-dimensional hierarchical clustering of selected genes. These data indicate that transformation of Barrett's esophagus to adenocarcinoma is associated with suppression of the genes involved in epidermal differentiation, including genes in 1q21 loci and corresponding to the epidermal differentiation complex. Correlation analysis of genes concordantly expressed in Barrett's esophagus and adenocarcinoma revealed 21 genes that represent potential genetic markers of disease progression and pharmacologic targets for treatment intervention. PCR analysis of genes selected based on DNA array experiments revealed that estimation of the ratios of GATA6 to SPRR3 allows discrimination among normal esophageal epithelium, Barrett's dysplasia, and adenocarcinoma.

The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis

“…GATA6 has also been reported to be involved in colorectal tumour invasion and in the conversion of Barrett metaplasia to adenocarcinoma 27,28 . Furthermore, GATA6 is known to be expressed in the proliferative crypt compartment of the small intestine, similar to Lgr5, although expression is found elsewhere as well 19,25 .…”

MMSET is overexpressed in cancers: Link with tumor aggressiveness

“…Overexpression of MMSET was found in glioblastoma compared to normal brain (P = 1.7E-14, P = .009, P = .002) [11; 12; 13]; in hepatocellular carcinoma compared to normal liver (P = 2.9E-7, 1.3E-6) [14; 15]; in head and neck cancer compared to the normal (P = .008, P = 2.7E-5) [16; 17]; in bladder carcinoma compared to normal bladder (P = 4.1E-11, P = 1.8E-7) [18; 19]; in primary colon cancer compared to normal adjacent mucosa (P = 9.5E-6) [20]; in esophagus adenocarcinoma compared to normal esophagus (P = .004) [21]; in breast carcinoma compared to normal breast (P = 3.8E-8) [22]; in T-cell acute lymphoblastic leukemia compared to normal bone marrow (P = 5.1E-7) [23]; in B-cell acute lymphoblastic leukaemia compared to normal bone marrow (P = .001) [23]; in lung adenocarcinoma compared to normal lung (P = .009, P = 8.4E-4, 1.7E-6) [24; 25; 26]; in lymphoma compared to normal B-cell (P = 3.5E-5, 7.3E-5) [27]; in cutaneous melanoma compared to normal melanocyte ( P = 6.46E-13, P = .01, P =.009) [28; 29; 30]; in smoldering multiple myeloma compared to normal bone marrow (P = 7.3E-4) [31]; in prostate cancer compared to normal prostate (P = 1.8E-6, P = .039, P = 5.1E-8, P = .002, P = .009, P = .006, P = .009) [32; 33; 34; 35; 36; 37; 38]; in yolk sac tumor compared to normal testis (P = .003) [39]; in ovarian carcinoma compared to normal ovary (P = .002, P = 1.1E-4) [40; 41] and in clear cell carcinoma compared to normal kidney tissue (P = .006) [42].…”

MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers

“…Our analysis of normal and esophageal tumor tissues demonstrates decreased ANXA1 expression with a concomitant increase in miR-196a levels in tumors compared to the matched normal tissue. In light of the report that ANXA1 mRNA levels progressively decrease from normal esophageal epithelium to Barrett's esophagus (BE) and from BE to adenocarcinoma (Kimchi et al, 2005), it would be interesting to determine if miR-196a level can be used as early marker of esophageal cancer. Though our study predominantly focused on esophageal adenocarcinomas, previous studies have reported an association between ANXA1 loss and tumorigenesis of squamous cell carcinoma of the esophagus (Paweletz et al, 2000;Xia et al, 2002;Hu et al, 2004).…”