携带自噬基因Beclin 1的嵌合型溶瘤腺病毒SG635-Beclin 1对肝癌的抑制作用

By carrying tumor suppressor genes, oncolytic adenoviruses could combine the advantages of gene therapy and virotherapy, which was the main model of cancer biotherapy at present. In our previous study, we had constructed 5/35 fiber chimeric oncolytic adenovirus carrying tumor suppressor genes, which not only specially enhanced antitumor ef?cacy on hepatocellular carcinoma (HCC) both in vivo and in vitro, but displayed little cytotoxicity to normal cells. Autophagy was described to be involved in multiple levels of tumor development, including cell cycle, apoptosis-related factors, angiogenesis and so on. Beclin 1 was recognized as a autophagy-related gene, and also was one of the most tumor suppressor genes. In our previous study , we found many HCC cell lines expresses less level of Beclin 1 than normal cells. So, we constructed a novel 5/35 fiber chimeric oncolytic adenovirus expressing Beclin 1, SG635-Beclin 1, based on the previously constructed oncolytic adenovirus vectors. We investigated the capacity of the new fiber chimeric oncolytic adenovirus to selectively replicate and overexpress the gene. Then we evaluated the cytotoxicity in HCC cell lines in vitro and in vivo experiments, and further explored its mechanism. Our study may serve as a novel, promising and safe anticancer agent for clincial cancer biotherapy of HCC.

溶瘤腺病毒携带抑癌基因治疗肿瘤联合了病毒治疗和基因治疗的双重优势，目前已经成为肿瘤生物治疗的一种重要模式。我们既往研究中已经构建出具有多重调控功能的可携带抑癌基因的5/35嵌合型溶瘤腺病毒，在体内体外可发挥较强的特异型抑制肝癌作用，同时对正常细胞作用轻微。有研究标明自噬可从多个层面影响肿瘤的发生发展，包括细胞周期、凋亡相关因子及血管生成等，Beclin 1是目前公认的自噬相关基因，是最重要的抑癌基因之一。我们前期发现Beclin 1在多个肝癌细胞系中相对于正常细胞表达偏低，因此我们拟在既往的溶瘤腺病毒载体基础上构建携带Beclin 1的5/35嵌合型溶瘤腺病毒SG635- Beclin 1，检测该病毒在肝癌细胞中的特异性增殖能力、扩增抑制基因能力和体外杀伤作用以及对肝癌裸鼠移植瘤的抑制作用，并进一步探讨其对肝癌治疗作用的机制，旨在为肝癌的临床生物治疗提供一个新的、效果显著同时副作用低的方法

溶瘤腺病毒携带抑癌基因治疗肿瘤联合了病毒治疗和基因治疗的双重优势，目前已经成为肿瘤生物治疗的一种重要模式。有研究标明自噬可从多个层面影响肿瘤的发生发展，包括细胞周期、凋亡相关因子及血管生成等，Beclin 1是目前公认的自噬相关基因，是最重要的抑癌基因之一。我们前期发现Beclin 1在多个肝癌细胞系中相对于正常细胞表达偏低，因此我们在既往的溶瘤腺病毒载体基础上构建携带Beclin 1的5/35嵌合型溶瘤腺病毒SG635- Beclin 1，检测该病毒在肝癌细胞中的特异性增殖能力、扩增抑制基因能力和体外杀伤作用以及对肝癌裸鼠移植瘤的抑制作用，并进一步探讨其对肝癌治疗作用的机制。结果发现，构建出新的嵌合型溶瘤腺病毒SG635-Beclin 1对肝癌细胞的感染能力、复制增殖能力以及扩增抑癌基因的能力显著，并在体内体外均显示出更强的抑制肝癌细胞的能力；同时SG635-Beclin 1在正常细胞中几乎不增殖对其没有杀伤作用，具有很好的安全性；SG635-Beclin 1对肝癌的治疗作用与病毒的靶向性杀伤作用和Beclin1基因诱导细胞发生自噬性死亡，从而抑制肿瘤细胞的增殖密切相关。新的溶瘤腺病毒SG635-Beclin 1为肝癌的临床生物治疗提供一个新的、效果显著同时副作用低的方法。