Loss of desmocollin-2 confers a tumorigenic phenotype to colonic epithelial cells through activation of Akt/β-catenin signaling

Abstract

This study provides evidence that decreased expression of the desmosomal cadherin desmocollin-2 enhances intestinal epithelial cell proliferation and promotes tumor formation via an Akt/β-catenin pathway.

Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling

“…7 To assess whether loss of Dsg2 influences colon cancer growth, we generated stable knockdown SK-CO15 cell lines expressing the Dsg2-specific short hairpin RNA (shDsg2) via lentivirus transduction and compared the proliferation of these cells with controls expressing the non-targeting shRNA (shControl) or Dsc2 knockdown clones (shDsc2) generated in parallel. Downregulation of Dsg2 and Dsc2 protein was confirmed by immunoblotting ( Figure 1a and Supplementary Figure 1a) and immunofluorescence labeling (data not shown).…”

“…[5][6][7] Our studies have been focused on understanding the functional role of Dsg2 and Dsc2 in intestinal epithelial cells, as expression of these proteins is altered in cancers and inflammatory diseases. [7][8][9][10] We recently demonstrated that loss of Dsc2 promoted colonic epithelial cell proliferation and tumor growth in vivo, 7 thus supporting a role of Dsc2 as a tumor suppressor in colon cancer. However, the contribution of Dsg2 to colon cancer cell growth is not known.…”

Structural and Functional Diversity of Desmosomes

“…While this example and others (Goonesinghe et al, 2012;Gehmlich et al, 2012;Cui et al, 2012;Den et al, 2006;Kolegraff et al, 2011;Chen et al, 2013) illustrated the broad impact of desmogleindesmocollin expression on organismal development and tissue homeostasis, much of the information pertaining to desmosomal cadherins and signaling stems from the study of a specifi c tissue, the epidermis. As noted above, the epidermis expresses all desmocollin and desmoglein isoforms, but does so in a manner which depends heavily upon the differentiation status of keratinocytes.…”

Desmoglein 2 Compensates for Desmoglein 3 but Does Not Control Cell Adhesion via Regulation of p38 Mitogen-activated Protein Kinase in Keratinocytes

“…This scenario is conceivable because Dsg2 is discussed to be associated with tumorigenesis in epithelial tissues (35,36) and has been implicated in the regulation of apoptosis in intestinal cells (23). Furthermore, loss of Dsc2 has been reported recently to contribute to malignant transformation of intestinal epithelial cells via activation of Akt/␤-catenin signaling (37). Thus, similar to classical cadherins, desmosomal cadherins should be recognized not only as adhesion molecules but, rather, as adhesion receptors with a variety of functions independent of their adhesive properties.…”