XAF1 as a prognostic biomarker and therapeutic target in pancreatic cancer
XAF1 as a prognostic biomarker and therapeutic target in pancreatic cancer
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DOI：
10.1111/j.1349-7006.2009.01396.x
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发表时间：
2010-02-01
期刊：
影响因子：
5.7
通讯作者：
Yuan, Yao-zong
中科院分区：
文献类型：
--
作者：
Huang, Jia;Yao, Wei-yan;Yuan, Yao-zong
XAF 1（X染色体连锁凋亡抑制因子[XIAP]相关因子1）是一种新型XIAP调节剂，其负调节XIAP的抗凋亡作用并使细胞对其他细胞死亡触发物敏感。据报道，它在多种人类癌细胞系中下调。然而，XAF 1在胰腺癌发生中的作用仍不清楚。在本研究中，我们研究了XAF 1表达的预后价值及其在体外和体内癌细胞生长和凋亡中的调节。组织芯片免疫组化染色显示，89例胰腺组织中有40例（44.9%）XAF 1呈低水平表达。统计学分析显示，XAF 1表达下调与肿瘤分期显著相关（P = 0.047），低水平XAF 1表达的患者生存期较短（P = 0.0162）。多因素分析显示XAF 1表达是胰腺癌患者生存的独立预后指标（P = 0.007）。此外，我们发现，由Ad 5/F35病毒介导的XAF 1表达的恢复抑制细胞增殖，诱导细胞周期停滞和凋亡，伴随着半胱氨酸蛋白酶3，8和9和聚（ADP-核糖）聚合酶的激活，以及细胞色素c和Bid裂解水平的增加。值得注意的是，XAF 1恢复强烈降低生存素表达，而不是XIAP。此外，体内s.c.来自Ad 5/F35-XAF 1处理的异种移植物显示出较少的细胞增殖和增强的凋亡，其显著小于来自对照组的那些。我们的研究结果表明，XAF 1是胰腺癌的一个有价值的预后标志物，并可能成为癌症基因治疗的潜在候选者。（Cancer Sci 2010; 101：559-567）
XAF1 (X chromosome-linked inhibitor of apoptosis [XIAP]-associated factor 1) is a novel XIAP modulator that negatively regulates the anti-apoptotic effects of XIAP and sensitizes cells to other cell death triggers. It has been reported to be downregulated in a variety of human cancer cell lines. However, the role of XAF1 in pancreatic carcinogenesis remains unclear. In the present study, we investigated the prognostic values of XAF1 expression and its regulation in cancer cell growth and apoptosis both in vitro and in vivo. From the immunohistochemistry staining of tissue microarray, 40 of 89 (44.9%) pancreatic specimens showed low levels of XAF1 expression. Statistical analysis suggested the downregulation of XAF1 was significantly correlated with tumor staging (P = 0.047) and those patients with low XAF1 levels had shorter survival times (P = 0.0162). Multivariate analysis indicated that XAF1 expression was an independent prognostic indicator of the survival of patients with pancreatic cancer (P = 0.007). Furthermore, we found that restoration of XAF1 expression mediated by Ad5/F35 virus suppressed cell proliferation and induced cell cycle arrest and apoptosis, accompanied by the activation of caspases 3, 8, and 9 and poly(ADP-ribose) polymerase as well as increased level of cytochrome c and Bid cleavage. Notably, XAF1 restoration robustly decreased survivin expression rather than XIAP. In addition, in vivo s.c. xenografts from Ad5/F35-XAF1 treatment, which showed less cellular proliferation and enhanced apoptosis, were significantly smaller than those from control groups. Our findings document that XAF1 is a valuable prognostic marker in pancreatic cancer and could be a potential candidate for cancer gene therapy. (Cancer Sci 2010; 101: 559-567)