Troy is expressed in human stomach mucosa and a novel putative prognostic marker of intestinal type gastric cancer

Abstract

Epithelial stem cells of gastrointestinal tissues are characterized and controlled by an active Wnt signaling. Recently, the Wnt target gene Troy has been proposed as a neoplastic marker in the murine intestine. In this study, we explored the putative tumor biological significance of Troy in humans by using immunohistochemistry (104 cases), quantitative RT-PCR (50 cases) and cell culture experiments (MKN45, MKN74). In the non-neoplastic gastric mucosa, Troy was expressed by Muc5AC-positive foveolar epithelium, parietal cells, chief cells and cells of the intestinal metaplasia. In gastric cancer, Troy was found in the desmoplastic stroma and tumor cells. The overall staining intensity of the tumor cells was lower compared with the adjacent non-neoplastic mucosa, Troy was found significantly more commonly in intestinal compared with diffuse type gastric cancer (p=0.001) and correlated inversely with tumor grade (p<0.001) and nodal spread (p=0.025). In the intestinal type, loss of Troy-expression was associated with a significantly worse overall survival (p=0.006). Subsequent cell culture experiments showed a Wnt dependent expression of Troy and a reduced colony formation ability of Troy-overexpressing MKN45-cells. Our results lead to the conjecture that Troy is also a negative regulator of WNT signaling in gastric cancer, which affects patient outcome.