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失调的Notch 信号与癌基因ras共同促进肝细胞转化与增殖
作者:范任华 陈平圣  
单位:东南大学
关键词:Notch 信号  Ras 肝细胞 转化 增殖 
分类号:
出版年·卷·期(页码):2011·30·第四期(568-572)
摘要:

摘要:目的:研究失调的Notch 信号与癌基因Ras共同作用对正常肝细胞转化和增殖的影响。方法:通过构建Notch1、 Ras的重组载体NICD-pEGFP-C1、H-Ras-pEGFP-C1,然后共转染正常肝细胞系L02;用MTT法及克隆形成实验检测细胞增殖能力;体内致瘤实验了解细胞转化状况。 结果: MTT检测结果显示外源性Notch1-ICD能促进L02细胞的增殖,与癌基因Ras共转染能显著增加L02细胞的增殖;γ-分泌酶抑制剂DAPT处理共转染的L02细胞,结果显示随DAPT浓度增加细胞增殖活性呈依赖性减低;克隆形成实验显示共转染外源性的Notch1-ICD,Ras能促进L02细胞克隆形成;体内致瘤实验显示Ras与Notch1共同作用能促进L02细胞转化。结论:失调的Notch 信号与癌基因Ras共同作用促使正常肝细胞转化和增殖,从而导致肝细胞恶性转变,同时抑制Notch 信号、Ras两条信号转导通路可能是肝癌治疗的新策略。

Abstract: Aim: Recent studies have implicated aberrant Notch signaling in human hepatocellular carcinoma (HCC). Yet, relatively little is known about the role of wild type Notch signaling in human hepatocarcinogenesis. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. Notch-Ras cooperation promotes hepatic cells carcinogenesis is not documented yet. Methods: The correlations and biological effects of Notch1 and Ras were analyzed introducing recombinant vectors NICD-pEGFP-C1 and/or H-Ras-pEGFP-C1 to human non-tumor hepatic cell line L02 cells. The viability of L02 cells transfected with recombinant vector was performed by MTT and the proliferation of L02 cells was tested using clone assay. The transformation of L02 cells was evaluated in vivo. Results: MTT assay showed that forced overexpression of Notch1-ICD and H-Ras promotes proliferation and growth than unmanipulated L02 cells (P<0.01). Cells treated with DAPT showed a significant reduction in cell viability compared with controls (P<0.01). Constitutively active Notch1 alone failed to transform immortalized L02 cells in vivo, it synergized with the Ras pathway to promote hepatic cells transformation (P<0.01). Conclusions: We showed that Ras-Notch signaling cooperation drives hepatic cells transformation and stimulates proliferation. Dysregulated Notch signaling cooperation with the Ras in transformation and proliferation offers combined inhibition of the two pathways as an attractive avenue for therapeutic intervention for this advanced disease. Key words Notch signaling, Ras, transformation, proliferation, hepatocarcinogenesis Abbreviation: H-Ras-pEGFP-C1, H-Ras; NICD-pEGFP-C1, NICD; N-(N-[3,5-difluorophenacetyl]-L-alanyl)-Sphenylglycine t-butyl ester, DAPT

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