Abstract
Abstract
Alteration of tumor suppressor gene function often leads to imbalance in expression of angiogenic and angiostatic factors facilitating disease progression. TP73, a member of the p53 tumor suppressor gene family, regulates many important cellular pathways and has been shown to be abnormally expressed in non-Hodgkin's lymphoma (NHL). TP73 gene function is controlled by harmony between two isoforms with opposing functions, the full length TAp73 protein (pro-apoptotic) and the NH2-terminally truncated ΔNp73 protein (anti-apoptotic through antagonizing both TAp73 and p53). We have observed differential ΔNp73 up-regulation and increase in ΔNp73:TAp73 expression ratio among NHL cases with 1p36 chromosomal disruption as compared to NHL cases without 1p36 disruption, which is associated with aggressiveness. To decipher whether deregulated p73 isoforms expression modulates the angiogenic potential in NHL we examined the mRNA expression of angiogenic factors (VEGF-A, FGF-2, and angiogenic chemokine CXCL-8) and angiostatic factors (TSP-1 and Endostatin) in NHL cases with and without chromosome 1p36 abnormality by real-time PCR. We observed higher levels of expression of angiogenic factors (VEGF-A, FGF-2, and CXCL-8) and lower levels of angiostatic factors (TSP-1 and Endostatin) in NHL cases with 1p36 abnormality as compared to NHL cases without 1p36 abnormality. Next, we performed a non-parametric bivariate correlation analysis (Kendall's tau_b and Spearman's rho) to examine whether ΔNp73:TAp73 expression ratio correlates with the expression of angiogenic and angiostatic factors. We observed a significant correlation between ΔNp73:TAp73 expression ratio with the expression of VEGF-A (r=0.900, p<0.001), FGF-2 (r=0.620, p<0.05) and TSP-1 (r=−0.873, p<0.001). To further elucidate the relationship between differential p73 isoforms expression and the expression pattern of angiogenic and angiostatic factors, we stably transfected an NHL cell line with 1p36 disruption, Granta-519 (TAp73 non expressor) with a wild type TAp73 mammalian expression vector. We observed an up-regulation of TSP-1 and Endostatin expression among Granta-519 cells transfected with TAp73 vectors compared to isogenic control vector transfected cells. Our data highlights the molecular and functional consequences of the differential p73 isoforms expression pattern caused by 1p36 chromosomal disruption on angiogenic phenotype in NHL.
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 222. doi:10.1158/1538-7445.AM2011-222