Tu Shui Ping, Liston Peter, Cui Jian Tao, Lin Marie C M, Jiang Xiao Hua, Yang Yi, Gu Qing, Jiang Shi Hu, Lum Ching Tung, Kung Hsiang Fu, Korneluk Robert G, Wong Benjamin Chun-Yu
Department of Gastroenterology, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, People's Republic of China.
Int J Cancer. 2009 Aug 1;125(3):688-97. doi: 10.1002/ijc.24282.
XAF1 (XIAP-associated factor 1) is a novel XIAP binding protein that can antagonize XIAP and sensitize cells to other cell death triggers. Our previous results have shown that aberrant hypermethylation of the CpG sites in XAF1 promoter is strongly associated with lower expression of XAF1 in gastric cancers. In our study, we investigated the effect of restoration of XAF1 expression on growth of gastric cancers. We found that the restoration of XAF1 expression suppressed anchorage-dependent and -independent growth and increased sensitivity to TRAIL and drug-induced apoptosis. Stable cell clones expressing XAF1 exhibited delayed tumor initiation in nude mice. Restoration of XAF1 expression mediated by adenovirus vector greatly increased apoptosis in gastric cancer cell lines in a time- and dose-dependent manner and sensitized cancer cells to TRAIL and drugs-induced apoptosis. Adeno-XAF1 transduction induced cell cycle G2/M arrest and upregulated the expression of p21 and downregulated the expression of cyclin B1 and cdc2. Notably, adeno-XAF1 treatment significantly inhibited tumor growth, strongly enhanced the antitumor activity of TRAIL in a gastric cancer xenograft model in vivo, and significantly prolonged the survival time of animals bearing tumor xenografts. Complete eradication of established tumors was achieved on combined treatment with adeno-XAF1 and TRAIL. Our results document that the restoration of XAF1 inhibits gastric tumorigenesis and tumor growth and that XAF1 is a promising candidate for cancer gene therapy.
XAF1（X连锁凋亡抑制蛋白相关因子1）是一种新型的X连锁凋亡抑制蛋白结合蛋白，它能够拮抗X连锁凋亡抑制蛋白，并使细胞对其他细胞死亡触发因素敏感。我们之前的研究结果表明，XAF1启动子中CpG位点的异常高甲基化与胃癌中XAF1的低表达密切相关。在本研究中，我们调查了XAF1表达恢复对胃癌生长的影响。我们发现，XAF1表达的恢复抑制了贴壁依赖性和非贴壁依赖性生长，并增加了对肿瘤坏死因子相关凋亡诱导配体（TRAIL）和药物诱导凋亡的敏感性。表达XAF1的稳定细胞克隆在裸鼠中表现出肿瘤起始延迟。腺病毒载体介导的XAF1表达恢复以时间和剂量依赖性方式极大地增加了胃癌细胞系中的凋亡，并使癌细胞对TRAIL和药物诱导的凋亡敏感。腺病毒-XAF1转导诱导细胞周期G2/M期阻滞，上调p21的表达，下调细胞周期蛋白B1和细胞周期蛋白依赖性激酶2（cdc2）的表达。值得注意的是，腺病毒-XAF1治疗显著抑制肿瘤生长，在体内胃癌异种移植模型中强烈增强TRAIL的抗肿瘤活性，并显著延长荷瘤异种移植动物的存活时间。腺病毒-XAF1与TRAIL联合治疗实现了对已建立肿瘤的完全根除。我们的结果证明，XAF1表达的恢复抑制胃癌发生和肿瘤生长，并且XAF1是癌症基因治疗的一个有前景的候选者。
