A genome-wide microRNA screen identifies regulators of tetraploid cell proliferation

被引:12
作者
Vittoria, Marc A. [1 ]
Shenk, Elizabeth M. [1 ,3 ]
O'Rourke, Kevin P. [4 ]
Bolgioni, Amanda F. [1 ]
Lim, Sanghee [1 ]
Kacprzak, Victoria [1 ]
Quinton, Ryan J. [1 ]
Ganem, Neil J. [1 ,2 ]
机构
[1] Boston Univ, Sch Med, Dept Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02118 USA
[2] Boston Univ, Sch Med, Dept Med, Div Hematol & Oncol, Boston, MA 02118 USA
[3] Boston Univ, Dept Biomed Engn, Boston, MA 02118 USA
[4] Rockefeller Univ, Weill Cornell Med, Sloan Kettering Triinst MD PhD Program, New York, NY 10065 USA
基金
美国国家卫生研究院; 加拿大健康研究院;
关键词
ORGAN SIZE CONTROL; HIPPO PATHWAY; CHROMOSOMAL INSTABILITY; PROMOTES TUMORIGENESIS; TISSUE HOMEOSTASIS; MAMMALIAN-CELLS; YAP ONCOPROTEIN; CANCER; FAILURE; POLYPLOIDY;
D O I
10.1091/mbc.E18-02-0141
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Tetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that similar to 40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, non-transformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these antiproliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive gain-offunction genome-wide screen to identify microRNAs (miRNAs) that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g., miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g., miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via down-regulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.
引用
收藏
页码:1682 / 1692
页数:11
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