mTOR Signaling Pathway Is a Target for the Treatment of Colorectal Cancer
mTOR Signaling Pathway Is a Target for the Treatment of Colorectal Cancer
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DOI：
10.1245/s10434-009-0555-9
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发表时间：
2009-09-01
影响因子：
3.7
通讯作者：
Fang, Jing-Yuan
中科院分区：
文献类型：
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作者：
Zhang, Yan-Jie;Dai, Qiang;Fang, Jing-Yuan
背景mTOR信号转导被认为是肿瘤发生的重要因素，但其在结直肠癌（CRC）中的作用尚未完全阐明。因此，本研究的目的是分析mTOR信号组分在CRC和腺瘤中的分布模式，并确定靶向抑制mTOR是否可能成为CRC的潜在治疗策略。对人CRC和腺瘤进行了mTOR信号成分（包括mTOR、p70 s6 K和4EBP 1）的免疫组织化学分析。用针对mTOR的siRNA处理HCT 116和SW480人CRC细胞系，并评估细胞活力、细胞周期和细胞凋亡。将HCT 116和SW 480细胞注射到无胸腺裸鼠中以建立CRC异种移植物模型。将小鼠随机转染非靶向对照或mTOR siRNA，并评估肿瘤体积、mTOR信号传导活性和细胞凋亡。mTOR信号成分，包括mTOR、p70s6 K和4EBP 1，在结直肠癌和结直肠腺瘤的腺体成分中高度活化，伴有高度上皮内瘤变（HIN），在结直肠癌中染色强度与浸润深度之间存在相关性。使用特异性mTOR siRNA抑制mTOR表达导致体外和体内细胞生长显著降低。mTOR信号传导与人CRC的临床病理学参数相关。siRNA介导的mTOR基因沉默可能是CRC的一种新的治疗策略。
Background. mTOR signaling has been suggested to be an important factor involved in tumorigenesis, but its role in human colorectal cancer (CRC) has not been completely elucidated. Herein, the purpose of this study was to analyze the distribution pattern of mTOR signaling components in CRC and adenoma and to determine whether targeted inhibition of mTOR could be a potential therapeutic strategy for CRC.Methods. Immunohistochemical analysis was performed on human CRC and adenoma for mTOR signaling components, including mTOR, p70s6 K, and 4EBP1. HCT116 and SW480 human CRC cell lines were treated with siRNA directed against mTOR, and cell viability, cell cycle, and apoptosis were assessed. HCT116 and SW480 cells were injected into athymic nude mice to establish a CRC xenograft model. Mice were randomly transfected with either nontargeting control or mTOR siRNA, and tumor volume, mTOR signaling activity, and apoptosis were evaluated.Results. mTOR signaling components, including mTOR, p70s6 K, and 4EBP1, were highly activated in glandular elements of CRC and colorectal adenomas with high-grade intraepithelial neoplasia (HIN), with a correlation between staining intensity and depth of infiltration in CRC. Inhibition of mTOR expression using a specific mTOR siRNA resulted in considerably decreased in vitro and in vivo cell growth.Conclusions. mTOR signaling is associated with the clinical pathological parameters of human CRC. siRNA-mediated gene silencing of mTOR may be a novel therapeutic strategy for CRC.