However, these efforts have not yielded convincing evidence that these genes are the principal mediators of the distal phenotype in this disease 7, 8. A substantial research effort has been invested in investigating the role of CDX genes in positional misspecification in BE 6. Regulation of rostral-caudal patterning of specialized tissue in embryology and adulthood is to a large extent dependent on the concerted action of two evolutionary highly conserved gene systems, the Caudal-related Homeobox ( CDX) transcription factor gene family and the genes of the Homeobox ( HOX) cluster. Therefore, dysregulation of positional specification is likely involved in the etiology of BE. Therefore, a deeper understanding of the biology of BE and gastric IM is necessary for designing rational avenues for the prevention and treatment of GI cancers.īE is characterized by the presence of cells with a caudal intestinal phenotype at a rostral location.
Similarly, while absolute risk is low, heterotopic tissues in Meckel’s diverticula and gastric inlet patches of the proximal esophagus represent relatively high-risk regions for adenocarcinoma comparatively to other sites of the ileum and proximal esophagus, respectively 4, 5. pylori-infection can degenerate into atrophic gastritis and gastric IM, which in turn can progress into gastric cancer, the third leading cause of cancer-related death 3. BE is a precursor lesion for esophageal adenocarcinoma (EAC) 1, 2, a disease which has shown a strong increase in incidence in the past decades. In the esophagus, the chronic inflammation associated with gastroesophageal reflux disease (GERD) is believed to lead to Barrett’s esophagus (BE), a crypt-structured columnar epithelium with distal gastrointestinal (GI)-tract characteristics, located just above the gastro-esophageal junction (GEJ). 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.īarrett’s esophagus (BE) and gastric intestinal metaplasia (IM) are important risk factors for adenocarcinoma of the esophagus and stomach. Additionally, we observe that HOXA13 expression confers a competitive advantage to cells. 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.
HOXA13 overexpression appears sufficient to explain both the phenotype (through downregulation of the epidermal differentiation complex) and the oncogenic potential of Barrett’s esophagus. Here we show HOX collinearity in the adult gut while Barrett’s esophagus shows high HOXA13 expression in stem cells and their progeny.
HOX genes are known mediators of position-dependent morphology. Nature Communications volume 12, Article number: 3354 ( 2021)īarrett’s esophagus in gastrointestinal reflux patients constitutes a columnar epithelium with distal characteristics, prone to progress to esophageal adenocarcinoma.
HOXA13 in etiology and oncogenic potential of Barrett’s esophagus
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