Hedgehog and epithelial‐mesenchymal transition signaling in normal and malignant epithelial cells of the esophagus

Abstract

It has been established that the Hedgehog (Hh) and epithelial-mesenchymal transition (EMT) signals act on morphogenesis of embryonic and adult tissues. Recently, both signals have been involved in tumor malignancy. However, little is known as to whether Hh and EMT signals act on normal and malignant epithelial cells in the esophagus. By laser microdissection (LMD)-based microarray and reverse transcription polymerase chain reaction in the undifferentiated and differentiated epithelial cells of the esophagus, we compared the expression profiles of Hh and EMT signaling molecules of these cells with those of cancers. Whether and how both signalings act in undifferentiated cells and in cancer cells are investigated by treatment of a Hh-signal inhibitor and/or siRNAs of Hh and EMT transcriptional key regulator genes on a mouse primary culture and on human esophageal squamous cell carcinoma (ESCC) cell lines. Undifferentiated esophageal epithelial cells and most ESCCs coexpressed Hh and EMT signaling genes. Some mesenchymal-related genes were regulated by an EMT regulator SIP1/ZEB2/ZFHX1B, which was a downstream gene of a primary transcriptional transducer GLI1 in Hh signaling. Hh signal block inhibited esophageal keratinocyte differentiation and cancer cell invasion and growth. These findings suggest that the mesenchymal gene expression of undifferentiated cells is maintained or strengthened in cancer cells through Hh signaling. This is a first report showing the presence of crosstalk between Hh and EMT pathways.