Inhibition of non-small cell lung cancer cell proliferation and tumor growth by vector-based small interfering RNAs targeting HER2/neu
Inhibition of non-small cell lung cancer cell proliferation and tumor growth by vector-based small interfering RNAs targeting HER2/neu
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DOI：
10.1016/j.canlet.2009.02.036
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发表时间：
2009-08-28
期刊：
影响因子：
9.7
通讯作者：
Yang, An-Gang
中科院分区：
文献类型：
--
作者：
Ren, Xin-Ling;Xu, Yan-Ming;Yang, An-Gang
HER2/neu癌基因的扩增和过表达存在于多种类型的人类癌症中，与肿瘤的发生、转移、血管生成和化疗耐药密切相关。在过去的几十年里，靶向HER2/neu的治疗药物已经得到了广泛的关注。在非小细胞肺癌（nsclc）中，HER2/neu激活的患病率、其在预后中的作用以及作为治疗靶点的可能意义仍有待阐明。在肺腺癌和肺大细胞癌细胞系中均可检测到HER2/neu的丰富或中度过表达。利用基于载体的小干扰rna （sirna）稳定敲低NSCLC细胞系SPC-A-1中HER2/neu的表达，导致细胞增殖和克隆形成效率显著降低，细胞周期阻滞在G期。与亲代非小细胞肺癌细胞相比，HER2/neu敲低细胞在裸鼠体内的肿瘤发育能力减弱，其移植瘤的生长明显下降。这些数据提供了直接证据，证明HER2/neu信号通路对NSCLC细胞的致瘤性至关重要，并表明靶向HER2/neu的sirna可能为NSCLC的治疗提供一种新的治疗策略，特别是当与传统治疗方法联合使用时，或通过开发基于载体的多靶点sirna来协同促进癌变，例如EGFR和HER2/neu。2009爱思唯尔爱尔兰有限公司版权所有。
Amplification and over-expression of HER2/neu oncogene is found in diverse types of human cancers, and is closely related to tumor occurrence, metastasis, angiogenesis and chemotherapy resistance. Therapeutic agents targeting HER2/neu have been intensively addressed over the past decades. In non-small cell lung cancers (NSCLCs), the prevalence of HER2/neu activation, its role in prognosis, and its possible implications as a therapeutic target, are still to be elucidated. Here we show that the abundant or moderate over-expression of HER2/neu could be detected in both pulmonary adenocarcinoma and pulmonary large cell carcinoma cell lines. Stable knockdown of HER2/neu expression in the NSCLC cell line SPC-A-1 was achieved by vector-based small interfering RNAs (siRNAs), which consequently caused significant decrease in cell proliferation and clone forming efficiency, as well as cell cycle arrest at G, phase. Compared with the parental NSCLC cells, HER2/neu knockdown cells exhibited attenuated capacities in developing tumors in nude mice, and the growth tumors xenografts derived from these cells were dramatically regressed. These data provided direct evidence that HER2/neu signaling is essential for tumorigenicity of NSCLC cells, and suggested that siRNAs targeted to HER2/neu may provide a novel therapeutic strategy in the treatment of NSCLC, especially when combined with traditional therapeutics or via development of vector-based siRNAs of multiple targets that synergistically contribute to carcinogenesis, e.g. EGFR and HER2/neu. (C) 2009 Elsevier Ireland Ltd. All rights reserved.