Hedgehog signal activation in esophageal epithelium and in tumor

Abstract

2674

Background & Aims: It has been established that Hedgehog ( Hh ) signal acts on both embryonal development and homeostasis and differentiation of the various adult tissue. However, in the esophagus, Hh signal activation remain unclear. In this study, we investigated whether Hh signal pathway is activated in the esophageal epithelium and tumors. Methods: By RT-PCR and immunohistochemical analysis, we investigated expression of many Hh signaling molecules in three layers of epithelium, the basal, epibasal, and differentiated, and also in esophageal squamous cell carcinomas ( ESCCs ). The effect of a Hh-pathway-specific inhibitor cyclopamine on a mouse primary culture and human esophageal cancer cell lines was investigated. Results: Hh signal activation through SHH and DHH was found in the basal and epibasal cells but not in the differentiated cells. Inhibition of the Hh signaling by cyclopamine in the mouse primary culture resulted in a decrease of differentiated cells. In ESCCs, 80% showed Hh signal activation through not only SHH and DHH expression but also cancer-linked IHH expression, and 17% showed that through a ligand free mechanism. Cyclopamine treatment inhibited cell growth of Hh signal-activated ESCCs. Conclusions: All the present data suggest that the Hh signal activation is required for esophageal epithelial cell differentiation, and that most ESCCs showed Hh signal activation. This type of cancer could be a therapeutic target of the Hh-pathway-specific inhibitors.