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STAT3反义寡核苷酸对人肺腺癌裸鼠移植瘤生长的抑制作用
孙顶,蔡建明*,祝宝让,程赢,李百龙,崔建国
0
(第二军医大学海军医学系防原医学教研室,上海 200433)
摘要:
目的探讨我们自行设计的STAT3(signal transducer and activator of transcription 3) 反义核酸(ASODN)对裸鼠肺腺癌A549细胞移植瘤的成瘤能力和移植瘤的抑制作用。方法将经全硫代修饰的STAT3 ASODN加入到培养的A549细胞内,CCK8法检测细胞生长的抑制率,然后将这种细胞接种于裸鼠颈部皮下,观察肿瘤出现的时间和肿瘤体积的变化,并计算成瘤率。同时取未经处理的A549细胞接种于裸鼠颈部皮下建立移植瘤模型,待瘤结节直径大于5 mm后,分为STAT3 ASODN实验组、生理盐水组和无义寡核苷酸对照组。实验组用15 mg/kg ASODN每天1次直接瘤内注射,连续3周,隔日测量肿瘤大小。处理30 d后,剥离瘤块称质量。蛋白质免疫印迹法检测肿瘤中STAT3、pSTAT3的表达。结果STAT3 ASODN显著抑制A549细胞生长,与无义寡核苷酸组相比,差异有统计学意义(P<0.05)。STAT3 ASODN作用后的A549细胞在裸鼠皮下成瘤能力明显降低,抑瘤率达75.8%。在各组荷瘤动物模型中,生理盐水对照组和无义寡核苷酸对照组的瘤体进行性增大,而STAT3 ASODN处理组的瘤块生长缓慢,与2个对照组相比均有差异(P<0.01),处理30 d后,ASODN处理组的肿瘤质量与2个对照组相比差异均有统计学意义(P<0.05),STAT3 ASODN处理组裸鼠A549细胞移植瘤的生长明显受到抑制,抑瘤率为51.1%。肿瘤中STAT3蛋白表达水平以及磷酸化水平也明显下调。结论STAT3 ASODN能降低A549细胞的成瘤率、抑制移植瘤生长。
关键词:  反义寡核苷酸类  STAT3  肺肿瘤  腺癌  肿瘤移植  抑瘤作用
DOI:10.3724/SP.J.1008.2011.076
投稿时间:2010-03-30修订日期:2010-12-22
基金项目:国家自然科学基金(30470415).
Inhibitory effect of STAT3 antisense oligodeoxynucleotide against human adenocarcinoma of lung derived from A549 cell in nude mice
SUN Ding,CAI Jian-ming*,ZHU Bao-rang,CHENG Ying,LI Bai-long,CUI Jian-guo
(Department of Atomic Irradiation Prevention, Faculty of Navy Medicine, Second Military Medical University, Shanghai 200433, China)
Abstract:
ObjectiveTo investigate the inhibitory effects of antisense oligodeoxynucleotide(ASODN) of signal transducer and activator of transcription 3 (STAT3) on development and growth of transplanted lung A549 cell adenocarcinoma in nude mice. MethodsThe inhibitory effects of STAT3 ASODN on A549 cell growth was evaluated by CCK8 assay. STAT3 ASODNtreated A549 cells were implanted subcutaneously into nude mice; the tumor growth was observed and the tumorforming rate was calculated. After subcutaneous implantation of the untreated A549 cells, the tumorbearing mice were randomized into 3 groups: control group, STAT3 ASODN group, and nonsense oligodeoxynucleotide (NSODN) group, with normal saline, STAT3 ASODN, and STAT3 NSODN injected intatumorally (15 mg/kg daily for 3 weeks). The tumor volumes were measured every other day and the tumor weights were determined. The protein expressions of STAT3 and pSTAT3 in xenografts were examined by Western blotting analysis. ResultsSTAT3 ASODN significantly inhibited the growth of A549 cells compared with STAT3 NSODN group (P<0.05). The tumor formation ability of A549 cells treated with STAT3 ASODN was significantly decreased (with the tumor inhibitory rate being 75.8%). Moreover, the growth of transplanted tumor was also significantly inhibited in STAT3 ASODN group as compared with those in NSODN group and control group (P<0.05) . The tumor weights were significantly reduced in STAT3 ASODN group than in STAT3 NSODN group and control group (with the tumor inhibitory rate being 51.1%). The expression of STAT3 protein and pSTAT3 was also downregulated in STAT3 ASODN group. ConclusionSTAT3 ASODN can suppress the tumorigenic ability of A549 cells and inhibit the growth of transplanted tumor in nude mice.
Key words:  antisense oligonucleotides  STAT3  lung neoplasms  adenocarcinoma  neoplasm transplantation  antitumor effect