Impact of Deoxycholic Acid on Oesophageal Adenocarcinoma Invasion: Effect on Matrix Metalloproteinases

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.

Research Progress of Bile Acids in Cancer

“…Halvorsen et al also obtained similar results, that LCA promoted the secretion of matrix metalloproteinase 2 (MMP-2) and increased cellular invasion in human colon cancer cells (80). For DCA, several studies have confirmed its ability to promote invasion/migration in colon cancer and esophageal adenocarcinoma, but only at a low concentration (20 mM) (82,83). Pai et al concluded that at doses of 5 and 50 mM, DCA can enhance the invasiveness of colon cancer cells by activating b-catenin-cyclin D1 and -uPAR signaling pathways (55).…”

“…also obtained similar results, that LCA promoted the secretion of matrix metalloproteinase 2 (MMP-2) and increased cellular invasion in human colon cancer cells ( 80 ). For DCA, several studies have confirmed its ability to promote invasion/migration in colon cancer and esophageal adenocarcinoma, but only at a low concentration (20 μM) ( 82 , 83 ). Pai et al.…”

“…For example, Quilty et al. concisely described the phenomenon that high-dose (200 μM) DCA inhibits the invasiveness of esophageal adenocarcinoma in a study ( 83 ). Pyo et al.…”

“…When it comes to the anti-invasive/metastatic potential of bile acids, UDCA bears the brunt due to its therapeutic properties (although reports are limited), but the role of other bile acids cannot be ruled out. For example, Quilty et al concisely described the phenomenon that high-dose (200 mM) DCA inhibits the invasiveness of esophageal adenocarcinoma in a study (83). Pyo et al proposed for the first time that a physiological concentration (100 mM) of DCA can frustrate the invasion and migration of gastric carcinoma cells through the inhibition of Snail and MMP9, as well as the induction of Ecadherin and MUC2 (84).…”

Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases

“…MMP-2 and MMP-9 are calcium-dependent zinc-containing endopeptidases that belong to the MMP family. MMPs are thought to play an important role in cell behavior, such as proliferation, migration (adhesion or dispersion), differentiation, angiogenesis, apoptosis, and host defense [ 33 , 34 , 35 , 36 , 37 ]. MMPs are involved in the disruption of the extracellular matrix in ischemic strokes, which leads to changes in the blood vessel wall and may loosen the matrix around cells, facilitating cellular swelling [ 38 ].…”