Epithelial-Cadherin and β-Catenin Expression Changes in Pancreatic Intraepithelial Neoplasia

Abstract

Purpose: Cadherins and associated catenins are important mediators of epithelial cell-cell adhesion, as well as the Wnt-signaling pathway. Significant changes in their expression or structure have been implicated in malignancy. This study aimed to investigate the epithelial-cadherin (Ecadherin) and ␤-catenin expression changes during multistage, pancreatic ductal carcinogenesis.Experimental Design: Ninety-four Whipple resection specimens were retrieved from the surgical pathology files of the University Health Network (Toronto, Canada), from which tissue microarray blocks containing 36 pancreatic ductal adenocarcinomas, 34 PanIN-1A lesions, 28 PanIN-1B lesions, 27 PanIN-2 lesions, 16 PanIN-3 lesions, and 32 normal ducts were constructed. The E-cadherin, ␤-catenin, and the phosphorylated glycogen synthase kinase-3␤ of the Wnt/ ␤-catenin pathway were immunohistochemically evaluated in these duct/PanIN lesions.Results: There was marked increase in the cytoplasmic E-cadherin expression in PanIN lesions (P < 0.0001) and adenocarcinoma (P ‫؍‬ 0.005) compared with normal pancreatic ducts. In contrast, reduced/loss of E-cadherin membranous expression was also significant in ductal adenocarcinoma compared with both the PanIN lesions (P < 0.0001) and normal ducts (P ‫؍‬ 0.05). The ␤-catenin expression showed significantly more frequent aberrant nuclear localization in high-grade PanIN lesions, particularly PanIN2 and in adenocarcinoma compared with normal ducts or low grade PanIN lesions (P < 0.0001). However, there was a lack of correlation between phospho Ser9 -glycogen synthase kinase-3␤ cytoplasmic expression and ␤-catenin aberrant nuclear expression (P ‫؍‬ 0.07).Conclusions: Aberration in the expression of Ecadherin and its associated ␤-catenin is evident in preinvasive (PanIN) neoplastic pancreatic duct cells, suggesting involvement of pathways leading to ␤-catenin stabilization during pancreatic duct cell carcinogenesis.

Expression of the E-cadherin-catenin complex in patients with pancreatic ductal adenocarcinoma.

“…Then, they are transferred to the cell nucleus where they bind to the transcription factors TCF/LEF-1, thus affecting the expression of target genes. Some authors have observed nuclear expression of β-catenin in pancreatic cancer, which could indicate that carcinogenesis is also associated with the Wnt pathway [17,18]. We observed a distinct loss of membranous and cytoplasmic β-catenin expression and no nuclear reaction with GSK-3β, which could suggest that the Wnt pathway had not been activated and free catenins had been degraded with GSK-3 involvement.…”

Absence of the Major Zymogen Granule Membrane Protein, GP2, Does Not Affect Pancreatic Morphology or Secretion

“…ZG16p and GP2 are both major constituents of the submembranous matrix purfied from zymogen granules, potentially serving a role in protein sorting or granule formation (15). Muclin is a membrane protein present in the zymogen granule that also contains a ZP domain and has also been proposed to play a role in protein sorting (27). When quantitative protein immunoblotting was performed to compare the relative amounts of syncollin, ZG16p, and muclin to amylase in zymogen granules, there was no significant difference between wild-type and GP2-deficient mice (Fig.…”

In vitro Modeling of Human Pancreatic Duct Epithelial Cell Transformation Defines Gene Expression Changes Induced by K-ras Oncogenic Activation in Pancreatic Carcinogenesis

“…The assays were done using Stratagene MX3000P (La Jolla, CA). The relative quantification of gene expression was determined using the comparative C T method as described previously (25)(26)(27). The values of 18S rRNA were used to normalize the expression data.…”