Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147.

Abstract

UNLABELLED:

Epithelial cell-cell contacts maintain normal glandular tissue homeostasis, and their breakage can trigger epithelial-to-mesenchymal transition (EMT), a fundamental step in the development of metastatic cancer. Despite the ability of C-type lectin domains (CTLD) to modulate cell-cell adhesion, it is not known if they modulate epithelial adhesion in EMT and tumor progression. Here, the multi-CTLD mannose receptor, Endo180 (MRC2/uPARAP), was shown using the Kaplan-Meier analysis to be predictive of survival outcome in men with early prostate cancer. A proteomic screen of novel interaction partners with the fourth CTLD (CTLD4) in Endo180 revealed that its complex with CD147 is indispensable for the stability of three-dimensional acini formed by nontransformed prostate epithelial cells (PEC). Mechanistic study using knockdown of Endo180 or CD147, and treatment with an Endo180 mAb targeting CTLD4 (clone 39.10), or a dominant-negative GST-CTLD4 chimeric protein, induced scattering of PECs associated with internalization of Endo180 into endosomes, loss of E-cadherin (CDH1/ECAD), and unzipping of cell-cell junctions. These findings are the first to demonstrate that a CTLD acts as a suppressor and regulatory switch for EMT; thus, positing that stabilization of Endo180-CD147 complex is a viable therapeutic strategy to improve rates of prostate cancer survival.

IMPLICATIONS:

This study identifies the interaction between CTLD4 in Endo180 and CD147 as an EMT suppressor and indicates that stabilization of this molecular complex improves prostate cancer survival rates.

• Authors: Mercedes Rodriguez-Teja, Julian H Gronau, Ai Minamidate, Steven Darby, Luke Gaughan, Craig Robson, Francesco Mauri, Jonathan Waxman, Justin Sturge
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 13 Issue 3 Pg. 538-47 (Mar 2015) ISSN: 1557-3125 [Electronic] United States
• PMID: 25381222 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• BSG protein, human
• MRC2 protein, human
• Mannose-Binding Lectins
• Membrane Glycoproteins
• Receptors, Cell Surface
• Basigin

Topics

• Basigin (metabolism)
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition
• Humans
• Male
• Mannose-Binding Lectins (chemistry, metabolism)
• Membrane Glycoproteins (chemistry, metabolism)
• Prognosis
• Prostatic Neoplasms (chemistry, metabolism, pathology)
• Proteomics
• Receptors, Cell Surface (chemistry, metabolism)
• Survival Analysis