Regulation of oestrogen signalling by the receptor tyrosine kinase cKIT stabilises Barrett's oesophagus pre-malignant state.

Abstract

The pre-malignant precursor to oesophageal adenocarcinoma (OAC), Barrett's oesophagus (BO), is prevalent in 10-15% of patients with chronic gastroesophageal acid reflux. However, in most cases, the BO condition is stable to cancer promotion; i.e. less than 1% of patients develop OAC. Here, we investigate whether there are factors that can act to prevent BO patients from developing OAC. The receptor tyrosine kinase, cKIT, is expressed in Barrett's tissue, but sparingly so in either normal or OAC tissue. To investigate whether cKIT influences cellular function that might be consistent with sustaining BO, we knocked out the KIT gene. Gene Ontology analysis revealed that cells deleted for cKIT showed differentially expressed genes (DEGs) affecting functions associated with intercellular interactions and tight junction formation. Further analysis of DEGs showed that the absence of cKIT, as well as treatment with acid and bile salts, affected genes associated with oestrogen signalling. Under these conditions, the tight junction protein Occludin was found to translocate to the nucleus. Thus, the cKIT receptor, through regulating intracellular oestrogen signalling, affects cellular tight junction formation. Reducing cKIT function in BO tissue potentially leads to elevated permeability and exposure of basal and stromal cells to luminal noxious agents which could act as OAC promoters.