Prognostic Impact of ΔTAp73 Isoform Levels and Their Target Genes in Colon Cancer Patients

Purpose: Cumulative data support the role of Delta TAp73 variants in tumorigenic processes such as drug resistance. We evaluate the impact of TP73 isoforms and their putative target genes ABCB1, HMGB1, and CASP1 on the survival of colon cancer patients and the correlation between their expressions. Experimental Design: We determined in 77 colon cancer patients the expression of Delta Ex2p73, Delta Ex2/3p73, Delta Np73, TAp73, ABCB1, HMGB1, and CASP1 by quantitative real-time reverse transcriptase-PCR. Tumor characteristics, disease-free survival, and overall survival (OS) were examined in each patient. Functional experiments were carried out to check whether ectopic expression of DNp73 modifies the proliferation, drug resistance, migration, and invasion properties of colon tumor cells and the expression of ABCB1, HMGB1, and CASP1. Results: Positive correlations were observed between the expression levels of Delta TAp73 variants and HMGB1. Furthermore, a trend was observed for ABCB1. Overexpression of Delta Ex2/3p73 and Delta Np73 isoforms was significantly associated with advanced stages (P = 0.04 and P = 0.03, respectively) and predicted shortened OS (P = 0.04 and P = 0.05, respectively). High levels of ABCB1 and HMGB1 were associated with shorter OS (P = 0.04 and P = 0.05, respectively). Multivariate analysis showed that, in addition to the tumor stage, ABCB1 and HMGB1 had independent relationships with OS (P = 0.008). Ectopic expression of Delta Np73 was associated with an increase in proliferation and drug resistance. Conclusions: The positive correlation between Delta TAp73 variants and HMGB1 and ABCB1 expression supports them as TP73 targets. The fact that upregulation of Delta TAp73 isoforms was associated with shortened OS, increase in proliferation, and drug resistance confirms their oncogenic role and plausible value as prognostic markers. ABCB1 and HMGB1, putative Delta TAp73 target genes, strongly predict OS in an independent manner, making clear the importance of studying downstream TP73 targets that could predict the outcome of colon cancer patients better than Delta TAp73 variants themselves do. Clin Cancer Res; 17(18); 6029-39. (C) 2011 AACR.