The induction of endoreduplication and polyploidy by elevated expression of 14-3-3γ
Cecil J. Gomes1,2, Sara M. Centuori1, Michael W. Harman7,8, Charles W. Putnam3, Charles W. Wolgemuth4,5 and Jesse D. Martinez1,6
1 University of Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA
2 Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, Arizona, USA
3 Department of Surgery, University of Arizona, Tucson, Arizona, USA
4 Department of Physics, University of Arizona, Tucson, Arizona, USA
5 Department of Molecular & Cellular Biology, University of Arizona, Tucson, Arizona, USA
6 Department of Cell & Molecular Medicine, University of Arizona, Tucson, Arizona, USA
7 Department of Surgical Research, Rhode Island Hospital, Providence, Rhode Island, USA
8 Department of Engineering, Brown University, Providence, Rhode Island, USA
Correspondence:
Jesse D. Martinez, email:
Keywords: 14-3-3 gamma, polyploidy, chromosomal instability, aneuploidy, non-small cell lung cancer
Received: May 22, 2017 Accepted: December 03, 2017 Published: December 24, 2017
Abstract
Several studies have demonstrated that specific 14-3-3 isoforms are frequently elevated in cancer and that these proteins play a role in human tumorigenesis. 14-3-3γ, an isoform recently demonstrated to function as an oncoprotein, is overexpressed in a variety of human cancers; however, its role in promoting tumorigenesis remains unclear. We previously reported that overexpression of 14-3-3γ caused the appearance of polyploid cells, a phenotype demonstrated to have profound tumor promoting properties. Here we examined the mechanism driving 14-3-3γ-induced polyploidization and the effect this has on genomic stability. Using FUCCI probes we showed that these polyploid cells appeared when diploid cells failed to enter mitosis and subsequently underwent endoreduplication. We then demonstrated that 14-3-3γ-induced polyploid cells experience significant chromosomal segregation errors during mitosis and observed that some of these cells stably propagate as tetraploids when isolated cells were expanded into stable cultures. These data lead us to conclude that overexpression of the 14-3-3γ promotes endoreduplication. We further investigated the role of 14-3-3γ in human NSCLC samples and found that its expression is significantly elevated in polyploid tumors. Collectively, these results suggests that 14-3-3γ may promote tumorigenesis through the production of a genetically unstable polyploid intermediate.
