Loss of desmoglein 2 promotes tumorigenic behavior in pancreatic cancer cells

Abstract

The ability to maintain cell-cell adhesion is crucial for tissue integrity and organization. Accordingly, loss of cohesiveness plays a critical role in cancer invasion and metastasis. Desmosomes are cell junctions providing strong intercellular adhesive strength and dysregulation of desmosomal constituents contributes to cancer progression through altered cell signaling pathways. Here, we focused on the desmosomal adhesion molecules Desmoglein 2 (Dsg2) and Desmocollin 2 (Dsc2), and their contribution to migration and invasion in pancreatic cancer cells. Silencing of Dsg2 but not Dsc2 resulted in loss of cell cohesion and enhanced migration, and invasion of pancreatic adenocarcinoma cells. To identify potential pathways regulated by Dsg2, we performed kinase arrays and detected the activity of ERK and growth factor receptors to be significantly enhanced in Dsg2-deficient cells. Consequently, inhibition of ERK phosphorylation in Dsg2 knockdown cells normalized migration. Loss of Dsg2 resulted in reduced levels of the desmosomal adapter protein and transcriptional regulator Plakoglobin (PG) in an ERK-dependent manner, whereas other desmosomal molecules were not altered. Overexpression of PG rescued enhanced migration induced by silencing of Dsg2. These results identify a novel pro-migratory pathway of pancreatic cancer cells in which loss of Dsg2 reduces the levels of PG via deregulated MAPK signaling.

Upregulation of desmoglein 2 and its clinical value in lung adenocarcinoma: a comprehensive analysis by multiple bioinformatics methods

“…DSG2 present in breast cancer cells may function as a tumor suppressor molecule (Davies et al, 1997). In pancreatic adenocarcinoma cells, silencing of DSG2 resulted in loss of cell cohesion and improved migration and invasion (Hutz et al, 2017). However, in colon cancers and NSCLC, knockdown DSG2 suppressed cell proliferation both in vitro and in vivo.…”

Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation

“…Dsg2 expression was upregulated in skin squamous cell carcinoma and head and neck cancer [14,15]. In contrast, Dsg2 expression was downregulated in pancreatic cancer, melanoma cells, and diffuse-type gastric cancer [16][17][18]. However, the expression level of Dsg2 and its potential role in GBC progression have not yet been reported.…”

A Five-Genes-Based Prognostic Signature for Cervical Cancer Overall Survival Prediction

“…International Journal of Genomics Intercellular adhesion plays an important role in the maintenance of multicellular structures and cell-cell signal transmission [50]. Desmosomes are intercellular connections that provide strong adhesion strength, and the dysregulation of desmosome components may lead to cancer progression International Journal of Genomics by altering cellular signalling pathways [51]. DSG2 is a transmembrane desmosomal cadherin [52].…”