摘要
目的研究射线诱导下Egr-1基因启动子调控腺病毒介导的Smad 7基因在C57BL/6J小鼠Lewis肺癌原发病灶内表达后,对原发灶及远处肺转移发生的影响.方法将Egr-1基因启动子的辐射敏感元件和Smad7 cDNA包装到复制缺陷型腺病毒内,制备成AD.Egr-Smad 7.接种Lewis肺癌细胞于小鼠右后肢外侧,建立荷瘤小鼠模型,肿瘤直径达0.8～1.0 cm时进行实验.小鼠被随机分入空白对照、生理盐水(NS)对照、AD.Egr-Smad7对照、单纯照射、NS+照射、AD.Eg-Smad 7+照射组(6只/组),分别进行如下研究:(1)隔日记录肿瘤长径及短径,观察肿瘤生长曲线、生长延迟时间及小鼠生存时间;(2)观察肿瘤照射2周时肺转移发生情况;(3)观察肿瘤生长至照射时4倍体积时肺转移发生情况.结果放射线诱导Egr-1基因启动子调控腺病毒介导的Smad 7基因在C57BL小鼠Lewis肺癌原发病灶内表达后,有抑制原发肿瘤生长及延长小鼠生存时间的作用(P＜0.05),对肿瘤远处肺转移的发生无明显影响(P＞0.05).结论放射线诱导AD.Egr-Smad 7无促进小鼠Lewis肺癌肿瘤局部病灶发展及远处脏器转移的危险性,并且有抑制原发肿瘤生长及延长生存时间的作用.将AD.Egr-Smad 7用于阻断TGF-β信号传导通路,靶向性基因治疗放射性肺纤维化具有一定的安全性.
Objective Objective To study the effect of adenovirus mediating Smad 7 gene regulated by radiation via Egr-1 on the primary tumor and lung metastasis in C57BL mice implanted with Lewis lung cancer. Methods The radio-inducible elements from the Egr-1 gene promoter were inserted upstream to a cDNA encoding Smad 7 and integrated into a replication-defective adenovirus to generate recombinant adenovirus （AD. Egr-Smad 7 ）. 270 mice implanted with Lewis lung cancer in the hind legs were used and the experiment was started when the transplanted tumor diameter reached 0.8 to 1.0 cm. Then three investigations were undertaken, each demanding 90 mice implanted with Lewis lung cancer respectively. To each group, 90 mice models were randomized into 3 groups： the normal control group; the NS control group; and the implanted AD. Egr-Smad 7 group. Every 6 mice in each group were irradiated by different single dose to study the following： 1. The maximal and minimal diameters of the tumor were recorded to observe the tumor growth tendency, the tumor growth delay and the mice survival time, 2. The incidence of lung metastasis two weeks after the radiation was recorded. 3. The incidence of lung metastasis when the tumor volume was four times as large as that at the beginning of radiation was recorded. Results The adenovirus mediating Smad 7 gene expression regulated by irradiation via Egr-1 in C57BL mice implanted with Lewis lung cancer was able to inhibit the progression of the primary tumor and prolong the survival of the mice significantly as compared with the control group （ P 〈 0.05 ）, though it could not significantly inhibit the lung metastasis（ P 〉 0.05）. Conclusions The gene expression of AD. Egr-Smad 7 regulated by radiation is not risky in promoting the local progression and distant metastasis of Lewis lung cancer in mice. On the other hand, the gene expression of AD. Egr-Smad 7 regulated by radiation could inhibit the progression of the primary tumor and prolong the sttrvival time of the mice significantly. It is safe,to some extent, of using AD.Egr-Smad 7 to block the signal transduction of TGF-βlocally as a novel strategy for gene therapy aiming at the prevention of radiation-induced lungfibrosis.
出处
《中华放射肿瘤学杂志》
CSCD
北大核心
2005年第5期439-442,共4页
Chinese Journal of Radiation Oncology
基金
国家自然科学基金资助项目(30170289)
