Servicio de Oncología Médica, Hospital Universitario Puerta de Hierro Majadahonda, Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
Clin Cancer Res. 2011 Sep 15;17(18):6029-39. doi: 10.1158/1078-0432.CCR-10-2388. Epub 2011 Aug 1.
Cumulative data support the role of ΔTAp73 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.
We determined in 77 colon cancer patients the expression of ΔEx2p73, ΔEx2/3p73, ΔNp73, 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 ΔNp73 modifies the proliferation, drug resistance, migration, and invasion properties of colon tumor cells and the expression of ABCB1, HMGB1, and CASP1.
Positive correlations were observed between the expression levels of ΔTAp73 variants and HMGB1. Furthermore, a trend was observed for ABCB1. Overexpression of ΔEx2/3p73 and ΔNp73 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 ΔNp73 was associated with an increase in proliferation and drug resistance.
The positive correlation between ΔTAp73 variants and HMGB1 and ABCB1 expression supports them as TP73 targets. The fact that upregulation of ΔTAp73 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 ΔTAp73 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 ΔTAp73 variants themselves do.
累积数据支持 ΔTAp73 变体在肿瘤发生过程中的作用，如耐药性。我们评估了 TP73 异构体及其假定的靶基因 ABCB1、HMGB1 和 CASP1 对结肠癌患者生存的影响及其表达之间的相关性。
我们通过定量实时逆转录聚合酶链反应确定了 77 例结肠癌患者中 ΔEx2p73、ΔEx2/3p73、ΔNp73、TAp73、ABCB1、HMGB1 和 CASP1 的表达。对每位患者的肿瘤特征、无病生存率和总生存率（OS）进行了检查。进行了功能实验以检查外源性表达 ΔNp73 是否改变了结肠肿瘤细胞的增殖、耐药性、迁移和侵袭特性以及 ABCB1、HMGB1 和 CASP1 的表达。
ΔTAp73 变体和 HMGB1 的表达水平之间存在正相关。此外，ABCB1 也呈现出一种趋势。ΔEx2/3p73 和 ΔNp73 异构体的过表达与晚期阶段显著相关（P = 0.04 和 P = 0.03），并预测 OS 缩短（P = 0.04 和 P = 0.05）。ABCB1 和 HMGB1 水平较高与 OS 缩短相关（P = 0.04 和 P = 0.05）。多变量分析表明，除了肿瘤分期外，ABCB1 和 HMGB1 与 OS 具有独立关系（P = 0.008）。ΔNp73 的异位表达与增殖和耐药性增加相关。
ΔTAp73 变体与 HMGB1 和 ABCB1 表达之间的正相关支持它们作为 TP73 靶标。ΔTAp73 异构体的上调与 OS 缩短、增殖增加和耐药性相关，证实了它们的致癌作用及其作为预后标志物的合理价值。ABCB1 和 HMGB1，推测的 ΔTAp73 靶基因，独立地强烈预测 OS，清楚地表明研究下游 TP73 靶标对于预测结肠癌患者的结局比 ΔTAp73 变体本身更好的重要性。
