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 epithelialmesenchymal 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. ' 2009 UICC

Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

“…SHH is active only in stem cells and/or endodermal progenitor in adults (16,23). Recent studies showed that aberrant signaling of this pathway is involved in a variety of human cancers (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). The HH pathway essentially consists of PTCH, the motive protein, SMOH, and the transcriptional factors GLI2 and GLI3.…”

“…Therefore, as a transcription factor, GLI1 expression is a good indicator of HH pathway activation. Recent studies showed that Gli1 controls several biological characteristics, such as proliferation and invasion, in several types of cancers (17,19,26).…”

“…The HH activation has been observed in other types cancers such as basal cell carcinomas of the skin (6-9), prostate cancer (10,11), lung cancer (12,13), gastrointestinal cancers (14)(15)(16)(17)(18)(19), breast cancer (20,21), and ovarian cancer (22). Although, it is required in liver embryogenesis (14,23), the HH signaling pathway is not well-sustained in the adult liver because of the insufficient HH pathway activity of mature hepatocytes (1,23).…”

Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: Implications for Alzheimer's disease

“…The Zfhx1b gene (44.810557 Mb), which encodes zinc finger homeobox 1b protein, showed the highest expression heritability correlation in the liver (r 5 -0.919, P < 4.99 -39 ), but none in brain. The Zfhxb1 protein is a Smad-interacting transcriptional corepressor involved in Wnt and hedgehog signaling (Bassez et al, 2004;Verstappen et al, 2008;Isohata et al, 2009). Detrimental variants of the gene cause the developmental disorder Mowat-Wilson syndrome, which presents with multiple congenital deficits, including mental retardation (Zweier et al, 2002).…”

Classification of epithelial–mesenchymal transition phenotypes in esophageal squamous cell carcinoma is strongly associated with patient prognosis

“…[5][6][7][8] Generally, the loss of E-cadherin is considered a common indicator for the onset of epithelial-mesenchymal transition, and it has been shown that Snail-dependent E-cadherin repression is one of the most important mechanisms for E-cadherin loss in esophageal squamous cell carcinoma. 5,8 However, there are some limitations in these studies due to the small number of cases investigated, and very little is known about the clinical significance of detailed epithelial-mesenchymal transition sub-phenotypes in esophageal squamous cell carcinoma.…”