The expression of Nectin-4 on the surface of ovarian cancer cells alters their ability to adhere, migrate, aggregate, and proliferate

Kristin L.M. Boylan, Petra C. Buchanan, Rory D. Manion, Dip M. Shukla, Kelly Braumberger, Cody Bruggemeyer, Amy P.N. Skubitz

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The cell adhesion molecule Nectin-4 is overexpressed in epithelial cancers, including ovarian cancer. The objective of this study was to determine the biological significance of Nectin-4 in the adhesion, aggregation, migration, and proliferation of ovarian cancer cells. Nectin-4 and its binding partner Nectin-1 were detected in patients' primary tumors, omental metastases, and ascites cells. The human cell lines NIH:OVCAR5 and CAOV3 were genetically modified to alter Nectin-4 expression. Cells that overexpressed Nectin-4 adhered to Nectin-1 in a concentration and time-dependent manner, and adhesion was inhibited by antibodies to Nectin-4 and Nectin-1, as well as synthetic Nectin peptides. In functional assays, CAOV3 cells with Nectin-4 knock-down were unable to form spheroids and migrated more slowly than CAOV3 parental cells expressing Nectin-4. NIH:OVCAR5 parental cells proliferated more rapidly, migrated faster, and formed larger spheroids than either the Nectin-4 knock-down or over-expressing cells. Parental cell lines expressed higher levels of epithelial markers and lower levels of mesenchymal markers compared to Nectin-4 knock-down cells, suggesting a role for Nectin-4 in epithelial-mesenchymal transition. Our results demonstrate that Nectin-4 promotes cell-cell adhesion, migration, and proliferation. Understanding the biology of Nectin-4 in ovarian cancer progression is critical to facilitate its development as a novel therapeutic target.

Original languageEnglish (US)
Pages (from-to)9717-9738
Number of pages22
JournalOncotarget
Volume8
Issue number6
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
We thank Dr. Marc Lopez for kindly providing the Flag-tagged Nectin-4 (Centre de Recherch? en Canc?rologie de Marseille, Marseille, France) and Dr. Robert Bast (MD Anderson Cancer Center University of Texas) for providing the CAOV3 cells. We thank Rachel Heinze, Ashley Mooneyham, and Kate Geschwind for technical assistance, and Dr. Subbaya Subramanian and the Department of Surgery at the University of Minnesota for the use of their BioTek Synergy Fluorescent Microplate reader. We also thank the University of Minnesota BioNet Tissue Procurement Facility for procuring the ovarian cancer samples. Funding was provided by the Minnesota Ovarian Cancer Alliance. This research was supported in part by NIH P30 CA77598 for use of the University of Minnesota Masonic Cancer Center's Flow Cytometry Shared Resource.

Keywords

  • Cell adhesion
  • Migration
  • Nectin-4
  • Ovarian cancer
  • Spheroids

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