Abstract
The homeodomain transcription factor PROX1 has been linked to several cancer types, including gliomas, but its functions remain to be further elucidated. Here we describe a functional role and the prognostic value of PROX1 in glioblastoma. Low expression of PROX1 correlated with poor overall survival and the mesenchymal glioblastoma subtype signature. The latter finding was recapitulated in vitro, where suppression or overexpression of PROX1 in glioma cell cultures transitioned cells to a mesenchymal or to a nonmesenchymal glioblastoma gene expression signature, respectively. PROX1 modulation affected proliferation rates that coincided with changes in protein levels of CCNA1 and CCNE1 as well as the cyclin inhibitors CDKN1A, CDKN1B, and CDKN1C. Overexpression of SOX2 increased PROX1 expression, but treatment with a CDK2 inhibitor subsequently decreased PROX1 expression, which was paralleled by decreased SOX2 levels. The THRAP3 protein was a novel binding partner for PROX1, and suppression of THRAP3 increased both transcript and protein levels of PROX1. Together, these findings highlight the prognostic value of PROX1 and its role as a regulator of glioblastoma gene expression subtypes, intratumoral heterogeneity, proliferation, and cell-cycle control.Significance: These findings demonstrate the role and prognostic value of PROX1 in glioblastomas; low PROX1 levels correlate with a mesenchymal gene expression subtype and shorter survival in glioblastoma tumors. Cancer Res; 78(20); 5901-16. ©2018 AACR.
Highlights
Glioblastoma represents the most common and aggressive primary brain tumor type in adults [1]
Given that CDK2 activity can stabilize SOX2 [38], we investigated if treatment of U-343 MGa cells with the CDK2 inhibitor CVT-313 compound would result in decreased Prospero-related homeobox 1 (PROX1) protein levels and found that CVT-313 treatment decreased both SOX2 and PROX1 protein levels within 24 hours (Fig. 7F)
In the light of recent findings about tumor heterogeneity and the intermixture of mesenchymal and nonmesenchymal gene expression subtype cells [4], the data present a mechanism of how these subtypes may be regulated by PROX1 during tumor cell evolution
Summary
Glioblastoma represents the most common and aggressive primary brain tumor type in adults [1]. Its intrusive growth and the plastic nature of the tumor make complete surgical resection impossible and the tumor cells prone to evade chemo- and radiation therapy [2]. Stem cell regulatory pathways are shown activated in gliomas supporting self-renewal, tumor maintenance, and survival under stress [3]. Glioblastomas are very heterogeneous on an intratumoral level, composed of tumor cells displaying different gene expression signatures constituting the different glioblastoma tumor subtypes [4]. A glioma stem-like phenotype, cell motility, and tumor cell heterogeneity are considered significant hurdles to overcome for developing new treatment against these tumors [5, 6]. Glioblastoma may arise from adult neural stem cells or multipotent neural progenitor cells that persist in proliferative niches in
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