Regulation of oestrogen signalling by the receptor tyrosine kinase cKIT stabilises the Barrett’s Oesophagus pre-malignant state
Description
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 Barrett’s Oesophagus condition is stable to progression. To establish a molecular basis for stabilisation of BO we identified that 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 inter-cell interactions and tight junction formation. Further analysis of DEGs showed that the absence of cKIT, and treatment with acid and bile acids, affected genes associated with oestrogen signalling. Under these conditions the tight junction protein, Occludin, which has previously been shown to be regulated by oestrogen, was found to translocate to the nucleus. Thus, the cKIT receptor through regulating intracellular oestrogen signalling affects cellular tight junction formation. Reducing cKIT function could lead to elevated permeability of BO tissue and exposure of basal and stromal cells to luminal noxious agents which could act as cancer promotors.