HOXA13 in etiology and oncogenic potential of Barrett's esophagus

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Janmaat, Vincent T. ; Nesteruk, Kateryna ; Spaander, Manon C. W. ; Verhaar, Auke P. ; Yu, Bingting ; Silva, Rodrigo A. ; Phillips, Wayne A. ; Magierowski, Marcin ; van de Winkel, Anouk ; Stadler, H. Scott ; Sandoval-Guzman, Tatiana ; van der Laan, Luc J. W. ; Kuipers, Ernst J. ; Smits, Ron ; Bruno, Marco J. ; Fuhler, Gwenny M. ; Clemons, Nicholas J. ; Peppelenbosch, Maikel P.

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 12, n. 1, p. 17-pg., 2021-06-07.

Abstract

Barrett's esophagus in gastrointestinal reflux patients constitutes a columnar epithelium with distal characteristics, prone to progress to esophageal adenocarcinoma. HOX genes are known mediators of position-dependent morphology. Here we show HOX collinearity in the adult gut while Barrett's esophagus shows high HOXA13 expression in stem cells and their progeny. HOXA13 overexpression appears sufficient to explain both the phenotype (through downregulation of the epidermal differentiation complex) and the oncogenic potential of Barrett's esophagus. Intriguingly, employing a mouse model that contains a reporter coupled to the HOXA13 promotor we identify single HOXA13-positive cells distally from the physiological esophagus, which is mirrored in human physiology, but increased in Barrett's esophagus. Additionally, we observe that HOXA13 expression confers a competitive advantage to cells. We thus propose that Barrett's esophagus and associated esophageal adenocarcinoma is the consequence of expansion of this gastro-esophageal HOXA13-expressing compartment following epithelial injury. Barrett's esophagus is a pro-oncogenic lesion in the proximal gastrointestinal tract, but with a distal colon-like morphology. Here the authors report that the distal HOX gene HOXA13 is expressed in Barrett's esophagus and in single cells of the physiological esophagus, and may underlie the phenotypic aspects of metaplasia and increase proliferation. (AU)

• FAPESP's process: 17/01046-5 - secRNA and DNA-methylome of osteoblast cells in response to paracrine effects od endothelial cells under a static and dynamic model.
• Grantee: Rodrigo Augusto da Silva
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 16/01139-0 - Epigenetic modulation triggered by paracrine factors from endothelial cells on osteoblast
• Grantee: Rodrigo Augusto da Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral