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Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research. In this review, we update recent progress in the research area of targeted therapy for ESCC. SOX2 and its associated proteins (e.g., ΔNP63α), which regulate lineage survival of ESCC cells, are proposed as therapeutic targets. It is believed that targeting the lineage-survival mechanism may be more effective than targeting other mechanisms. With the advent of a new era of personalized targeted therapy, there is a need to move from the tumor-centric model into an organismic model.

Mammalian esophagus exhibits a remarkable change in epithelial structure during the transition from embryo to adult. However, the molecular mechanisms of esophageal epithelial development are not well understood. Zebrafish (Danio rerio), a common model organism for vertebrate development and gene function, has not previously been characterized as a model system for esophageal epithelial development. In this study, we characterized a piece of non-keratinized stratified squamous epithelium similar to human esophageal epithelium in the upper digestive tract of developing zebrafish. Under the microscope, this piece was detectable at 5dpf and became stratified at 7dpf. Expression of esophageal epithelial marker genes (Krt5, P63, Sox2 and Pax9) was detected by immunohistochemistry and in situ hybridization. Knockdown of P63, a gene known to be critical for esophageal epithelium, disrupted the development of this epithelium. With this model system, we found that Pax9 knockdown resulted in loss or disorganization of the squamous epithelium, as well as down-regulation of the differentiation markers Krt4 and Krt5. In summary, we characterized a region of stratified squamous epithelium in the zebrafish upper digestive tract which can be used for functional studies of candidate genes involved in esophageal epithelial biology.

Background and Aims: Autophagy is a normal physiological mechanism for the degradation of cellular proteins and organelles. Excessive autophagy induced by cellular stress leads to cell death. However, the exact role of autophagy in cancer is not completely clear. Beclin1 plays a central role in the regulation of autophagy. The major goal of our study was to evaluate the role of Beclin-1 and autophagy and the effect of bile acids in the esophageal carcinogenesis. Barrett's esophagus (BE) is a premalignant lesion of distal esophagus associated with an increased risk for the development of esophageal adenocarcinoma (EAC). Methods: Beclin-1 expression was evaluated using immunohistochemistry, immunoblotting, or RTPCR in (1) biopsies obtained from 62 patients with BE or EAC, (2) tissues from a rat model of BE and EAC, and (3) esophageal cell lines. Since reflux of bile acids is important in esophageal carcinogenesis, the effect of acute and chronic exposure to deoxycholic acid (DCA) on autophagy and Beclin-1 expression was evaluated. Autophagy was assessed by electron microscopy or by transfection with GFP-LC3 plasmid and calculating the percentage of GFP-LC3 positive cells with punctuate pattern. Results: Our studies using human biopsies and rat tissues showed that Beclin-1 expression was high in squamous epithelium, while its expression was low in BE and EAC. A similar pattern was observed in esophageal cell lines. HET-1A cells (derived from normal squamous epithelium) showed high levels of Beclin-1, but lower levels of Beclin-1 were found in BE cells (CP-A, CP-C) and EAC cells (OE33 cells). Acute exposure to DCA led to increased Beclin-1 expression and increased autophagy in CP-A cells. In contrast, chronic exposure to DCA did not result in any alteration of Beclin-1 or autophagy. To demonstrate that Beclin-1 plays central role in autophagy we used siRNA to decrease Beclin-1 expression and then autophagy was evaluated after treatment with DCA. No increase in autophagy was detected compared to untreated control CP-A cells. Conclusions: In summary, our data suggests that autophagy is initially activated in response to bile acids, but chronic exposure to bile acids leads to decreased Beclin-1 expression and autophagy resistance. We propose that autophagy resistance in combination with apoptosis resistance induced by chronic exposure to bile acids contributes to EAC development.