P70S6K 1 regulation of angiogenesis through VEGF and HIF-1alpha expression.-猫眼课题宝

DOI：

10.1016/j.bbrc.2010.06.080

发表时间：

2010-07-30

期刊：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

影响因子：

3.1

通讯作者：

中科院分区：

生物学4区

文献类型：

作者：

Bian, Chuan-Xiu;Shi, Zhumei;Meng, Qiao;Jiang, Yue;Liu, Ling-Zhi;Jiang, Bing-Hua

关键词：

p70S6K1 VEGF HIF-1 Tumor angiogenesis siRNA

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928061/?report=classic

70 kDa核糖体S6激酶1（p70 S6 K1）是磷酸肌醇3-激酶（PI 3 K）和ERK丝裂原活化蛋白激酶（MAPK）的下游靶点，是细胞周期进程和细胞增殖的重要调节因子。最近的研究表明p70 S6 K1在PTEN阴性和AKT过表达的肿瘤中起重要作用。然而，p70 S6 K1在肿瘤血管生成中的作用机制仍有待阐明。在这项研究中，我们特异性地抑制p70 S6 K1在卵巢癌细胞中的活性，使用基于载体的小干扰RNA（siRNA）对p70 S6 K1。我们发现p70 S6 K1基因的敲低通过其增强子区域的HIF-1α结合位点显著降低VEGF蛋白表达和VEGF转录激活。p70 S6 K1 siRNA特异性抑制HIF-1α蛋白表达，但对HIF-1β蛋白表达无明显影响。我们还发现p70 S6 K1下调抑制卵巢肿瘤生长和血管生成，并降低肿瘤组织中细胞增殖和VEGF和HIF-1α表达水平。我们的研究结果表明p70 S6 K1通过HIF-1α和VEGF的表达参与肿瘤的生长和血管生成，从而提供了p70 S6 K1信号通路介导的人卵巢癌的分子机制。

The 70kDa ribosomal S6 kinase 1 (p70S6K1), a downstream target of phosphoinositide 3-kinase (PI3K) and ERK mitogen-activated protein kinase (MAPK), is an important regulator of cell cycle progression, and cell proliferation. Recent studies indicated an important role of p70S6K1 in PTEN negative and AKT-overexpressing tumors. However, the mechanism of p70S6K1 in tumor angiogenesis remains to be elucidated. In this study, we specifically inhibited p70S6K1 activity in ovarian cancer cells using vector-based small interfering RNA (siRNA) against p70S6K1. We found that knockdown of p70S6K1 significantly decreased VEGF protein expression and VEGF transcriptional activation through the HIF-1α binding site at its enhancer region. The expression of p70S6K1 siRNA specifically inhibited HIF-1α, but not HIF-1β protein expression. We also found that p70S6K1 down-regulation inhibited ovarian tumor growth and angiogenesis, and decreased cell proliferation and levels of VEGF and HIF-1α expression in tumor tissues. Our results suggest that p70S6K1 is required for tumor growth and angiogenesis through HIF-1α and VEGF expression, providing a molecular mechanism of human ovarian cancer mediated by p70S6K1 signaling.