title: CYR61 and TAZ Upregulation and Focal Epithelial to Mesenchymal Transition May Be Early Predictors of Barrett's Esophagus Malignant Progression.
abstract: Barrett's esophagus is the major risk factor for esophageal adenocarcinoma. It has a low but non-neglectable risk, high surveillance costs and no reliable risk stratification markers. We sought to identify early biomarkers, predictive of Barrett's malignant progression, using a meta-analysis approach on gene expression data. This in silico strategy was followed by experimental validation in a cohort of patients with extended follow up from the Instituto Português de Oncologia de Lisboa de Francisco Gentil EPE (Portugal). Bioinformatics and systems biology approaches singled out two candidate predictive markers for Barrett's progression, CYR61 and TAZ. Although previously implicated in other malignancies and in epithelial-to-mesenchymal transition phenotypes, our experimental validation shows for the first time that CYR61 and TAZ have the potential to be predictive biomarkers for cancer progression. Experimental validation by reverse transcriptase quantitative PCR and immunohistochemistry confirmed the up-regulation of both genes in Barrett's samples associated with high-grade dysplasia/adenocarcinoma. In our cohort CYR61 and TAZ up-regulation ranged from one to ten years prior to progression to adenocarcinoma in Barrett's esophagus index samples. Finally, we found that CYR61 and TAZ over-expression is correlated with early focal signs of epithelial to mesenchymal transition. Our results highlight both CYR61 and TAZ genes as potential predictive biomarkers for stratification of the risk for development of adenocarcinoma and suggest a potential mechanistic route for Barrett's esophagus neoplastic progression.
authors: Instituto Gulbenkian de Ciência, Oeiras, Portugal.|Ophiomics-Precision Medicine, Lisboa, Portugal.
authors: Joana
authors: http://orcid.org/0000-0002-8720-8845
authors: J
authors: Cardoso
authors: Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E., Lisboa, Portugal.|Faculdade de Ciências da Saúde-Universidade da Beira Interior, Covilhã, Portugal.
authors: Marta
authors: M
authors: Mesquita
authors: Faculdade de Ciências da Saúde-Universidade da Beira Interior, Covilhã, Portugal.|Serviço de Gastrenterologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E., Lisboa, Portugal.
authors: António
authors: A
authors: Dias Pereira
authors: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors: Mónica
authors: M
authors: Bettencourt-Dias
authors: Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E., Lisboa, Portugal.|Faculdade de Ciências da Saúde-Universidade da Beira Interior, Covilhã, Portugal.
authors: Paula
authors: P
authors: Chaves
authors: Instituto Gulbenkian de Ciência, Oeiras, Portugal.|Ophiomics-Precision Medicine, Lisboa, Portugal.
authors: José B
authors: JB
authors: Pereira-Leal
mesh_terms: D000217:Acyltransferases; D001471:Barrett Esophagus / Q000473:pathology*; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008297:Male; D016612:Paraffin Embedding; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D014157:Transcription Factors; D000217:Acyltransferases; C108675:TAFAZZIN protein, human