Activated Ras enhances insulin-like growth factor I induction of vascular endothelial growth factor in prostate epithelial cells.
Activated Ras enhances insulin-like growth factor I induction of vascular endothelial growth factor in prostate epithelial cells.
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DOI：
10.1158/0008-5472.can-04-4100
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发表时间：
2005-03
期刊：
影响因子：
11.2
通讯作者：
M. Stearns;J. Tran;M. K. Francis;Hong Zhang;C. Sell
中科院分区：
文献类型：
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作者：
M. Stearns;J. Tran;M. K. Francis;Hong Zhang;C. Sell
HRAS、KRAS和NRAS这三个密切相关的RAS基因的突变是人类癌症中发现的最常见的突变；在某些类型的癌症中，如结直肠癌，达到50%，在前列腺癌中达到10%。这些突变产生的激活的RAS蛋白可以增加血管内皮生长因子(VEGF)的产生，以及其他细胞变化。此外，携带RAS基因突变的肿瘤比不携带RAS基因突变的肿瘤血管更丰富。我们发现，在前列腺上皮细胞中，引入激活的HRAS会导致细胞产生血管内皮生长因子，以响应胰岛素样生长因子I(IGF-I)。相比之下，缺乏激活的RAS的细胞不能产生对IGF-I做出反应的血管内皮生长因子。RAS的这种作用可能是通过稳定第二信使蛋白，即胰岛素受体底物1来实现的，该信使蛋白介导PI3-激酶依赖的信号转导。由于IGF-I是一种旁分泌/内分泌激素，与几种类型癌症的风险增加有关，这些结果表明，HRAS等细胞基因的致癌转化与局部产生的IGF-I之间存在新的相互关系，以维持正常组织的动态平衡。
Mutations in the three closely related RAS genes, HRAS, KRAS, and NRAS are among the most common mutations found in human cancer; reaching 50% in some types of cancer, such as colorectal carcinoma, and 10% in prostate cancers. The activated Ras proteins produced by these mutations can, among other cellular changes, increase vascular endothelial growth factor (VEGF) production. Moreover, tumors bearing RAS gene mutations are more vascular than tumors without RAS mutations. We find that, in prostate epithelial cells, the introduction of an activated HRAS causes cells to produce VEGF in response to insulin-like growth factor I (IGF-I). In comparison, cells lacking an activated Ras are unable to produce VEGF in response to IGF-I. This effect of Ras may occur through stabilization of a second messenger protein, insulin receptor substrate 1, that mediates PI 3-kinase-dependent signaling. Because IGF-I is a paracrine/endocrine hormone that has been associated with increased risk for several types of cancer, these results suggest a novel interrelationship between oncogenic conversion of a cellular gene such as HRAS, and IGF-I produced locally for normal tissue homeostasis.