PNAS:联系正常身体生长和癌症的主控分子开关

来自美国国立卫生研究院的两位研究者已经发现了一个联健康胎儿的快速生长以及癌症中不受控制的细胞分裂的一个新基因.这项新研究的结果阐明了正常发育和常见癌症的遗传学基础.

该项目以小鼠和人类组织为研究对象,相关结果发表在PNAS杂志上.文章的作者是就职于施莱佛国家儿童健康与人类发展研究所(NICHD)的Julian C. Lui博士和Jeffrey Baron医学博士.

Baron博士说：“我们很早之前已经知道,一些能够促进产前和产后早期胎儿快速生长的基因会在癌细胞中变得异常活跃.现在,我们确定了一个分子开关,它可以开启这些基因中的一部分,这项研究结果为我们理解正常的身体发育以及某些类型癌症的异常生长奠定了基础.”

在出生之前,一组由超过200个促生长基因组成的基因组合是非常活跃的,它们启动了胎儿的迅速增长.在出生以后,这些基因的表达会被逐步的关闭,表现为随着年龄的生长和逐步接近成年,身体的生长会不断减缓；而在癌细胞中,这些基因的表达却被重新开启了.

其中一个最主要的促生长基因是胰岛素样生长因子(nsulin Growth Factor 2,IGF2 ),这种基因是产前胎儿正常的身体生长所必需的,但是它在许多类型的癌症中都会被重新激活,尤其在膀胱癌、前列腺癌以及一些儿童癌症中表现地极其活跃.

很多年来,科学家们都不知道是什么控制了IGF2的开启或关闭.现在,通过对一系列技术的利用以及对许多组织类型的研究,Lui和Baron发现证据表明,一个特殊的蛋白质——E2F3,激活了正常身体发育和癌症中的IGF2基因,特别是在膀胱癌和转移性的前列腺癌中.

更广泛的看,E2F3的调控对象不只有IGF2,还有其它许多促生长基因组合中的基因.当E2F3的水平很高时,它的调控对象是异常活跃的；当E2F3水平下降时,这些基因亦如此.从这点看,E2F3很可能作为一个限制身体生长的主控开关发挥关键作用.因此,它成为了研究人员理解正常生长和疾病的复杂遗传机制的最感兴趣的目标.（生物谷Bioon.com）

doi: 10.1073/pnas.1219079110
PMC:
PMID:

Evidence that Igf2 down-regulation in postnatal tissues and up-regulation in malignancies is driven by transcription factor E2f3

Julian C. Lui1 and Jeffrey Baron

Insulin-like growth factor 2 (IGF2) is an important fetal growth factor. Its expression is dramatically down-regulated in multiple organs after birth but is frequently up-regulated in cancers. The mechanisms that drive down-regulation of IGF2 in postnatal tissues or the up-regulation in malignancy are unclear. We found evidence that E2F transcription factor 3 (E2F3) drives these changes in expression. E2f3 mRNA expression, protein expression, and binding to the Igf2 promoter all decreased with age postnatally in multiple mouse organs. In late juvenile hepatocytes, restoration of high E2f3 expression restored high Igf2 expression, indicating a causal relationship, but this induction did not occur in fetal hepatocytes, which already have high E2f3 and Igf2 expression. Transient expression of E2f3 in both HEK293 cells and in late juvenile hepatocytes were able to activate reporter constructs containing the mouse Igf2 promoter P2, which includes consensus E2F-binding sites. In humans, microarray data revealed declines in E2F3 and IGF2 expression with age similar to the mouse. In addition, E2F3-overexpressing human prostate and bladder cancers showed increased IGF2 expression, and levels of E2F3 and IGF2 mRNA in these cancers were positively correlated. Taken together, the findings suggest that down-regulation of E2f3 with age helps drive the dramatic decline in Igf2 expression in postnatal organs, and E2F3 overexpression in human cancers induces IGF2 overexpression.

(责任编辑：zengchang)