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

Abstract

Purpose: Cumulative data support the role of DTAp73 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 DEx2p73, DEx2/ 3p73, DNp73, 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 DTAp73 variants and HMGB1. Furthermore, a trend was observed for ABCB1. Overexpression of DEx2/3p73 and DNp73 isoforms was significantly associated with advanced stages (P ¼ 0.04 and P ¼ 0.03, respectively) and predicted shortened OS (P ¼ 0.04 and P ¼ 0.05, respectively). High levels of ABCB1 and HMGB1 were associated with shorter OS (P ¼ 0.04 and P ¼ 0.05, respectively). Multivariate analysis showed that, in addition to the tumor stage, ABCB1 and HMGB1 had independent relationships with OS (P ¼ 0.008). Ectopic expression of DNp73 was associated with an increase in proliferation and drug resistance.Conclusions: The positive correlation between DTAp73 variants and HMGB1 and ABCB1 expression supports them as TP73 targets. The fact that upregulation of DTAp73 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 DTAp73 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 DTAp73 variants themselves do.

High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia

“…[16][17][18] Of interest, several alternative splice variants at the C termini (a-u) and N terminus (p73Dex2, p73Dex2/3, collectively called DTAp73) of p73 have been described in human hematologic malignancies, 19,20 and these isoforms may directly affect the DNp73/TAp73 ratio. Here, using specific probes for transcriptionally active (ie, TA) and inactive (ie, DN) isoforms, we evaluated the "pool" of TA and DNp73 transcripts, not distinguishing among the different C-termini or N-termini variants.…”

Ratio disruption of the Δ133p53 and TAp53 isoform equilibrium correlates with poor clinical outcome in intrahepatic cholangiocarcinoma

“…A significant correlation has been reported between overexpression of ∆N isoforms and a poor prognosis in cervical, colon and ovarian cancer (10)(11)(12)14), but not in CCA. The incidence of p53 gene mutations in ICC is approximately 41.6% (15), while there has been no report of mutation in p73.…”

Small-Molecule Prodigiosin Restores p53 Tumor Suppressor Activity in Chemoresistant Colorectal Cancer Stem Cells via c-Jun-Mediated ΔNp73 Inhibition and p73 Activation

“…The oncogenic N-terminally truncated isoform DNp73 is a dominant negative inhibitor of p73 and p53 (11)(12)(13). DNp73 levels correlate with poor overall survival in colorectal cancer patients (14). p73 transcriptional activity and tumor suppression is also blocked by mutant p53 binding (15,16).…”