Abstract
Bile acids (BAs) have been implicated in the development of oesophagitis, Barrett’s oesophagus and oesophageal adenocarcinoma (OAC). However, whether BAs promote cancer invasiveness has not been elucidated. We evaluated the role of BAs, in particular deoxycholic acid (DCA), in OAC invasion. Migration and invasiveness in untreated and BA-treated oesophageal SKGT-4 cancer cells were evaluated. Activity and expression of different matrix metalloproteinases (MMPs) were determined by zymography, ELISA, PCR and Western blot. Finally, human OAC tissues were stained for MMP-10 by immunohistochemistry. It was found that SKGT-4 cells incubated with low concentrations of DCA had a significant increase in invasion. In addition, MMP-10 mRNA and protein expression were also increased in the presence of DCA. MMP-10 was found to be highly expressed both in-vitro and in-vivo in neoplastic OAC cells relative to non-neoplastic squamous epithelial cells. Our results show that DCA promotes OAC invasion and MMP-10 overexpression. This study will advance our understanding of the pathophysiological mechanisms involved in human OAC and shows promise for the development of new therapeutic strategies.
Highlights
Common oesophageal complications of gastro-oesophageal reflux disease (GORD) include reflux oesophagitis and Barrett’s oesophagus (BO), which is a known risk factor for the development of oesophageal adenocarcinoma (OAC)
We found that matrix metalloproteinases (MMPs)-1, MMP-9 and MMP-10 are over-expressed in SKGT-4 cells compared to Het-1A cells indicating changes in MMP levels as a model of the progression of OAC
We found that MMP-10 is over-expressed in OAC tissue compared to normal squamous epithelium which is reflective of our in-vitro observations and indicates the translational relevance of this study
Summary
Common oesophageal complications of gastro-oesophageal reflux disease (GORD) include reflux oesophagitis and Barrett’s oesophagus (BO), which is a known risk factor for the development of oesophageal adenocarcinoma (OAC). It is thought about 10% of all GORD patients develop BO [1,2]. Proton pump inhibitors (PPIs) are very effective for healing reflux oesophagitis as they are the most potent inhibitors of gastric acid secretion.
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