Augello Claudia, Caruso Luca, Maggioni Marco, Donadon Matteo, Montorsi Marco, Santambrogio Roberto, Torzilli Guido, Vaira Valentina, Pellegrini Caterina, Roncalli Massimo, Coggi Guido, Bosari Silvano
Department of Medicine, Surgery and Dentistry, Division of Pathology, University of Milan, AO S Paolo e Fondazione IRCCS Ospedale Maggiore Policlinico, Regina Elena e Mangiagalli, Milan, Italy.
BMC Cancer. 2009 Apr 27;9:125. doi: 10.1186/1471-2407-9-125.
Similarly to other tumor types, an imbalance between unrestrained cell proliferation and impaired apoptosis appears to be a major unfavorable feature of hepatocellular carcinoma (HCC). The members of IAP family are key regulators of apoptosis, cytokinesis and signal transduction. IAP survival action is antagonized by specific binding of Smac/DIABLO and XAF1. This study aimed to investigate the gene and protein expression pattern of IAP family members and their antagonists in a series of human HCCs and to assess their clinical significance.
Relative quantification of IAPs and their antagonist genes was assessed by quantitative Real Time RT-PCR (qPCR) in 80 patients who underwent surgical resection for HCC. The expression ratios of XIAP/XAF1 and of XIAP/Smac were also evaluated. Survivin, XIAP and XAF1 protein expression were investigated by immunohistochemistry. Correlations between mRNA levels, protein expression and clinicopathological features were assessed. Follow-up data were available for 69 HCC patients. The overall survival analysis was estimated according to the Kaplan-Meier method.
Survivin and Livin/ML-IAP mRNAs were significantly over-expressed in cancer tissues compared to non-neoplastic counterparts. Although Survivin immunoreactivity did not correlate with qPCR data, a significant relation was found between higher Survivin mRNA level and tumor stage, tumor grade and vascular invasion.The mRNA ratio XIAP/XAF1 was significantly higher in HCCs than in cirrhotic tissues. Moreover, high XIAP/XAF1 ratio was an indicator of poor prognosis when overall survival was estimated and elevated XIAP immunoreactivity was significantly associated with shorter survival.
Our study demonstrates that alterations in the expression of IAP family members, including Survivin and Livin/ML-IAP, are frequent in HCCs. Of interest, we could determine that an imbalance in XIAP/XAF1 mRNA expression levels correlated to overall patient survival, and that high XIAP immunoreactivity was a poor prognostic factor.
与其他肿瘤类型相似，不受控制的细胞增殖与凋亡受损之间的失衡似乎是肝细胞癌（HCC）的一个主要不良特征。IAP家族成员是凋亡、胞质分裂和信号转导的关键调节因子。Smac/DIABLO和XAF1的特异性结合可拮抗IAP的生存作用。本研究旨在调查一系列人类肝癌中IAP家族成员及其拮抗剂的基因和蛋白表达模式，并评估其临床意义。
通过定量实时逆转录聚合酶链反应（qPCR）对80例行肝癌手术切除的患者进行IAP及其拮抗剂基因的相对定量分析。还评估了XIAP/XAF1和XIAP/Smac的表达比率。通过免疫组织化学研究Survivin、XIAP和XAF1蛋白的表达。评估mRNA水平、蛋白表达与临床病理特征之间的相关性。69例肝癌患者有随访数据。根据Kaplan-Meier方法估计总生存分析。
与非肿瘤组织相比，Survivin和Livin/ML-IAP mRNA在癌组织中显著过表达。虽然Survivin免疫反应性与qPCR数据无关，但Survivin mRNA水平升高与肿瘤分期、肿瘤分级和血管侵犯之间存在显著关系。肝癌中XIAP/XAF1的mRNA比率显著高于肝硬化组织。此外，在估计总生存时，高XIAP/XAF1比率是预后不良的指标，XIAP免疫反应性升高与较短生存期显著相关。
我们的研究表明，IAP家族成员，包括Survivin和Livin/ML-IAP的表达改变在肝癌中很常见。有趣的是，我们可以确定XIAP/XAF1 mRNA表达水平的失衡与患者总生存相关，高XIAP免疫反应性是一个不良预后因素。
