Survival outcome and EMT suppression mediated by a lectin domain interaction of Endo180 and CD147

Rodriguez-Teja, Mercedes; Gronau, Julian H.; Minamidate, Ai; Darby, Steven; Gaughan, Luke; Robson, Craig; Mauri, Francesco; Waxman, Jonathan; Sturge, Justin

Abstract

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.

Citation

Rodriguez-Teja, M., Gronau, J. H., Minamidate, A., Darby, S., Gaughan, L., Robson, C., Mauri, F., Waxman, J., & Sturge, J. (2015). Survival outcome and EMT suppression mediated by a lectin domain interaction of Endo180 and CD147. Molecular cancer research, 13(3), 538-547. https://doi.org/10.1158/1541-7786.mcr-14-0344-t

• Acceptance Date: Nov 1, 2014
• Online Publication Date: Nov 7, 2014
• Publication Date: 2015-03
• Deposit Date: Jan 28, 2016
• Publicly Available Date: Nov 23, 2017
• Journal: Molecular cancer research
• Print ISSN: 1541-7786
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 3
• Pages: 538-547
• DOI: https://doi.org/10.1158/1541-7786.mcr-14-0344-t
• Keywords: Epithelial-to-mesenchymal transition (EMT)
• Public URL: https://hull-repository.worktribe.com/output/384598
• Publisher URL: http://mcr.aacrjournals.org/content/13/3/538.long
• Additional Information: This is the authors accepted manuscript of an article published in Molecular cancer research, 2015, v.13 issue 3.
• Contract Date: Nov 23, 2017