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瘤性BRAF通过由分泌的蛋白质IGFBP7介导的途径诱导衰老和亡
Narendra Wajapeyee1, Ryan W Serra, Xiaochun Zhu
1Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cell
|February 13, 2008
概括
激活BRAFV600E瘤基因会触发IGFBP7的分泌,矛盾的是,它会阻止细胞生长. 这一发现为黑色素瘤的发展和潜在的治疗点提供了新的见解.
科学领域:
- 在瘤学瘤学.
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 瘤基因激活可以悖论地通过衰老或亡抑制细胞增殖.
- 介导这种效应的精确分子通路尚未完全理解.
研究的目的:
- 为了确定参与BRAFV600E诱导的人类初级细胞增殖阻断的基因.
- 阐明分泌蛋白在瘤基因中介衰老和亡中的作用.
主要方法:
- 在人类初级纤维细胞和黑色素细胞中进行全基因组RNA干扰查.
- 对BRAF-MEK-ERK信号通路的分析.
- 使用BNIP3L上调调节对细胞亡的评估.
- 在实验室测试重组IGFBP7 (rIGFBP7) 在黑色素瘤细胞系.
- 在异种移植小鼠的体内瘤抑制研究.
- 人体皮肤,瘤和黑色素瘤样本的免疫组织化学分析.
主要成果:
- 17个基因被确定为BRAFV600E介导的增殖阻断的关键基因.
- 胰岛素样生长因子结合蛋白7 (IGFBP7) 在BRAFV600E诱导的衰老和亡中起着至关重要的作用.
- BRAFV600E表达导致IGFBP7的合成和分泌,这抑制了BRAF-MEK-ERK的信号传递.
- 在IGFBP7上调节了BNIP3L的前性蛋白.
- rIGFBP7诱导BRAFV600E阳性黑色素瘤细胞的亡,并在体内抑制瘤生长.
- 失去IGFBP7表达被认为是黑色素瘤发展的关键事件.
结论:
- IGFBP7是BRAFV600E诱导的衰老和亡的关键媒介.
- IGFBP7通过自身隐性/隐性机制起作用,抑制瘤信号传递并促进细胞死亡.
- IGFBP7代表了BRAFV600E阳性黑色素瘤的潜在治疗标.
- 失去IGFBP7是黑色素瘤发生的一个重要因素.
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