Abstract 2331: Role of MMP expression in the effect of Plk4 on cell migration and invasion

Abstract

Abstract Plk4 is a haploinsufficient tumor suppressor in mice (Ko et al, Nature Genetics, 2005). Plk4+/− mouse embryonic fibroblasts (MEFs) spontaneously immortalize in culture and become tumorigenic by passage 15 (Rosario et al, PNAS, 2010). We investigated the secondary genetic alterations associated with tumorigenicity. Early passage (P3) Plk4+/+, P3 Plk4+/− and late passage (P15) Plk4+/− MEFs were compared by genome-wide expression array (Illumina). When differentially expressed genes were organized by biological function, increased cell proliferation and death (p=2.13E10-1.31E02, p = 2.52E07-1.14E02 respectively), and decreased cell motility (p = 3.74E07-1.27E02) in the P15 MEFs were predicted. An independent array analysis comparing tumorigenic (T) to nontumorigenic (NT) Plk4+/− MEFs showed a pattern of altered gene expression predictive of decreased motility in the T MEFs. These results suggested the hypothesis that Plk4 modulates cell motility. To directly test this hypothesis in functional assays we measured cell spreading, scratch-wound healing and transwell migration through Matrigel; in all these assays P3 Plk4+/− were inferior to P3 Plk4+/+ MEFs. We hypothesized that altered MMP expression was one mechanism for the difference observed in migration, and tested this by comparing MMP-13,-10 and -3 expression as shown in the Table. Plk4 status was associated with altered expression of MMPs; in particular, MMP-13 expression was confirmed to be significantly reduced in P3 Plk4+/− compared to P3 Plk4+/+ MEFs by RT-qPCR. Our results indicate that Plk4 regulates cell motility and invasion. One potential mechanism is through upregulation of MMP-3,-10, and -13 expression. To further elucidate the molecular mechanisms of Plk4 related carcinogenesis we will next directly determine the effect of Plk4 on MMP activity and correlate this with migration and invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2331. doi:10.1158/1538-7445.AM2011-2331