ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features
ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features
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DOI：
10.1158/0008-5472.can-05-1404
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发表时间：
2005-12-01
期刊：
影响因子：
11.2
通讯作者：
Takahashi, T
中科院分区：
文献类型：
--
作者：
Osada, H;Tatematsu, Y;Takahashi, T
具有神经内分泌特征的肺癌通常具有侵袭性，尽管潜在的分子机制在很大程度上仍有待确定。碱性螺旋-环-螺旋蛋白(ASHI)在正常胎儿肺神经内分泌细胞和含有神经内分泌成分的肺癌中表达，被认为与肺癌的发生有关。在本研究中，我们发现通过基于质粒的RNA干扰(RNAi)抑制ASHI的表达，通过G(2)-M细胞周期停滞和亚G(1)群体的聚集显著抑制ASHI表达的肺癌细胞的生长，这可能与caspase-9和caspase-7的切割有关。而未表达ASHI的肺癌细胞系和永生化的正常BEAS2B支气管上皮细胞不受影响。RNAi抗性突变体ASHI明显诱导从G(2)-M期阻滞中解救出来，表明RNAi具有靶向性作用。我们还建立了ASH1-RNAi腺病毒，该病毒不仅在体外对ASH1阳性的NCI-H460细胞的增殖有明显的抑制作用，而且在体内对ASH1阳性的NCI-H460细胞的生长也有明显的抑制作用。在携带ASHI-RNAi腺病毒的NCI-H460异种移植瘤中也观察到细胞凋亡水平升高。因此，本研究提示ASHI在肺癌的发生发展中起重要作用，并可能成为治疗具有神经内分泌特征的肺癌的有效靶点。(癌症研究2005年；65(23)：10680-5)。
Lung cancers with neuroendocrine features are usually aggressive, although the underlying molecular mechanisms largely remain to be determined. The basic helix-loop-helix protein, achaete-scute complex-like 1/achaete-scute homologue 1 (ASHI), is expressed in normal fetal pulmonary neuroendocrine cells and lung cancers with neuroendocrine elements and is suggested to be involved in lung carcinogenesis. In the present study, we show inhibition of ASHI expression by plasmid-based RNA interference (RNAi) to significantly suppress growth of lung cancer cells with ASHI expression through G(2)-M cell cycle arrest and accumulation of sub-G(1) populations, possibly linked to cleavage of caspase-9 and caspase-7. However, lung cancer cell lines without ASHI expression and immortalized normal BEAS2B bronchial epithelial cells were not affected. The RNAi-resistant mutant ASHI clearly induced rescue from G(2)-M arrest, suggesting a target-specific effect of RNAi. An ASH1-RNAi adenovirus was also established and significantly inhibited not only in vitro cell proliferation but also in vivo xenograft growth of ASH1-positive NCI-H460 cells. Elevated levels of apoptosis were also observed in NCI-H460 xenografts with the ASHI-RNAi adenovirus. The present study therefore suggests that ASHI plays a crucial role in lung cancer development and may be an effective therapeutic target in lung cancers with neuroendocrine features. (Cancer Res 2005; 65(23): 10680-5).