Adenovirus-mediated tBid overexpression results in therapeutic effects on p53-resistant hepatocellular carcinoma
Adenovirus-mediated tBid overexpression results in therapeutic effects on p53-resistant hepatocellular carcinoma
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DOI：
10.1002/ijc.22040
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发表时间：
2006-10-15
影响因子：
6.4
通讯作者：
Lai, Paul B. S.
中科院分区：
文献类型：
--
作者：
Miao, Ji;Chen, George G.;Lai, Paul B. S.
肝细胞癌（Hepatocellular carcinoma，HCC）是世界范围内最常见的恶性肿瘤之一，死亡率极高。由于常规治疗的成功是有限的，基因治疗可能是HCC管理的替代方案。我们早期的研究表明，Bid在HCC的发展中起着重要作用。我们研究的目的是评估使用截短的Bid（tBid）作为肝癌治疗的新疗法的可能性。在实验中使用两种HCC细胞系，Hep 3B和PLC/PRF/5。Hep 3B对p53耐药，而PLC/PRF/5对p53敏感。构建了含甲胎蛋白（AFP）启动子驱动的tBid基因的重组腺病毒Ad/AFPtBid。用Ad/AFPtBid感染的Hep 3B和PLC/PRF/5细胞均显示细胞活力显著降低。Ad/AFPtBid引起的细胞活力下降是由于HCC细胞的凋亡，通过增强半胱天冬酶的活性和增加细胞色素c的释放来证明。体内实验通过瘤内注射Ad/AFPtBid在接种Hep 3B的裸鼠中进行。Ad/AFPtBid注射显著抑制肿瘤生长，肿瘤组织显示TUNEL阳性细胞显著增加。我们的实验还证明Ad/AFPtBid仅针对AFP产生细胞，而不针对非AFP产生细胞。总之，这些结果表明，Ad/AFPtBid的引入不仅可以显著地而且特异性地杀死产生AFP的HCC细胞。Ad/AFPtBid诱导的肝癌细胞死亡是通过凋亡途径进行的，这可能与p53状态无关。(c)2006威利-利斯公司
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with a very high mortality. Because the success of the conventional therapies is limited, gene therapy may represent an alternative for HCC management. Our earlier study has shown that Bid plays a role in the development of HCC. The aim of our study is to evaluate the possibility of using truncated Bid (tBid) as a novel therapy for HCC treatment. Two HCC cell lines, Hep3B and PLC/PRF/5, were used in the experiment. Hep3B was a p53-resistant while PLC/PRF/5 a p53-sensitive. A recombinant adenovirus-Ad/AFPtBid, which contained a tBid gene driven by an a-fetoprotein (AFP) promoter, was constructed. Both Hep3B and PLC/PRF/5 cells infected with Ad/AFPtBid showed a significant decrease in cell viability. The decrease in cell viability by Ad/AFPtBid resulted from apoptosis of HCC cells, evident by enhanced activity of caspases and increased release of cytochrome c. In vivo experiment was performed by the intratumor injection of Ad/AFPtBid in nude mice inoculated with Hep3B. Ad/AFPtBid injection significantly inhibited tumor growth, and tumor tissues showed a marked increase in TUNEL-positive cells. Our experiment also demonstrated that Ad/AFPtBid only targeted AFP-producing cells but not those non-AFP producing cells. In conclusion, these results indicate that the introduction of Ad/AFPtBid can not only significantly but specifically kill HCC cells that produce AFP. The cell death induced by Ad/AFPtBid in HCC cells is via an apoptotic pathway that can be independent of p53 status. (c) 2006 Wiley-Liss, Inc.