Abstract
Abstract Malignant gliomas remain to be fatal and highly resistant to therapy. PROX1 is a transcription factor critical for embryonic development, with a role in cell cycle control and progenitor cell differentiation. PROX1 is highly relevant to study in relation to brain tumors due to its role in normal CNS development, where it leads to progenitor cell differentiation and initiation of neurogenesis. We have previously shown that PROX1 is expressed in human gliomas where there is a positive and statistically significant correlation between PROX1 expression and glioma tumor grade. We have also evaluated the prognostic value of PROX1 in a cohort of patients with grade II gliomas and found that a high number of PROX1 positive cells correlated significantly with poor outcome, a clinically important finding, as such predictors do not exist at present. The mechanism behind PROX1 overexpression in high-grade glioma and its functional consequences remain unclear. To this end we set out to study PROX1 effects on the behavior of glioma cells. We found that glioma cell lines in general expressed only low levels of PROX1 protein and mRNA. However, PROX1 was readily detected in the U343MGa Cl2:6 glioma cell line. This cell line also expresses GFAP and SOX2 and has features in common with glioma stem cells. Depletion of PROX1 in U343MGa Cl2:6 cells using siRNA had a marginal positive effect on cell proliferation in a short term assay. Furthermore, ectopic PROX1 impaired the ability of glioma cells to proliferate as indicated by reduced colony formation and decreased BrdU incorporation. We present experimental evidence showing that PROX1 induces p27. By regulating p27, PROX1 may block the activity of Cdk2/Cyclin E complex, and thus inhibit cell cycle progression. The functional consequences of PROX1 expression on the stemness, migration, and invasion phenotypes of glioma cells remain to be further investigated and preliminary results will be presented. Citation Format: Kaveh M. Goudarzi, Tamador Elsir, Monica Nistér, Mikael S. Lindström. Control and function of the PROX1 transcription factor in malignant glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2082. doi:10.1158/1538-7445.AM2015-2082
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