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

• Type of Material: Article
• Authors: R. Kamekura, Emory University; K.N. Kolegraff, Emory University; P. Nava, Center for Research and Advanced Studies; Roland Hilgarth, Emory University; M. Feng, Emory University; Charles Parkos, Emory University; Asma Nusrat, Emory University
• Language: English
• Date: 2014-09-04
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Macmillan Publishers Limited
• Final Published Version (URL): http://dx.doi.org/10.1038/onc.2013.442
• Title of Journal or Parent Work: Oncogene
• ISSN: 0950-9232
• Volume: 33
• Issue: 36
• Start Page: 4531
• End Page: 4536
• Grant/Funding Information: This work was supported by the 12th Glaxo-SmithKline International Award from Japan Society of Immunology and Allergology in Otolaryngology (RK), an American Gastroenterological Association Research Scholar Award (PN), a Crohn’s and Colitis Foundation of America Career Development Award (PN), a CONACyT grant 175854 (PN) and National Institutes of Health grants DK061379, DK072564 (CAP), DK055679, DK059888 (AN) and DDRDC DK064399.
• Keywords: EXPRESSION; ADHESION; desmocollin; Science & Technology; INHIBITION; cancer; intestinal epithelium; Genetics & Heredity; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; CARCINOMAS; APOPTOSIS; RECEPTOR; Desmosome; Cell Biology; EGFR; DSG2; desmoglein; Oncology
• Research Categories: Health Sciences, Oncology

Abstract

Desmosomal cadherins mediate cell-cell adhesion in epithelial tissues and have been known to be altered in cancer. We have previously shown that one of the two intestinal epithelial desmosomal cadherins, desmocollin-2 (Dsc2) loss promotes colonic epithelial carcinoma cell proliferation and tumor formation. In this study we show that loss of the other intestinal desmosomal cadherin, desmoglein-2 (Dsg2) that pairs with Dsc2, results in decreased epithelial cell proliferation and suppressed xenograft tumor growth in mice. Dsg2-deficient cells demonstrated a compensatory increase in Dsc2 expression, and small interfering RNA-mediated loss of Dsc2 restored proliferation in Dsg2-deficient cells. Dsg2 downregulation inhibited epidermal growth factor receptor (EGFR) signaling and cell proliferation through altered phosphorylation of EGFR and downstream extracellular signal-regulated kinase activation in parallel with inhibited EGFR receptor internalization. Additionally, we demonstrated a central role of Dsc2 in controlling EGFR signaling and cell proliferation in intestinal epithelial cells. Consistent with these findings, analyses of human colon cancers demonstrated increased Dsg2 protein expression. Taken together, these data demonstrate that partner desmosomal cadherins Dsg2 and Dsc2 play opposing roles in controlling colonic carcinoma cell proliferation through differential effects on EGFR signaling.