3-phosphoinositide-dependent protein kinase-1 (PDK1) promotes invasion and activation of matrix metalloproteinases.
3-phosphoinositide-dependent protein kinase-1 (PDK1) promotes invasion and activation of matrix metalloproteinases.
复制标题
DOI：
10.1186/1471-2407-6-77
复制
发表时间：
2006-03-21
期刊：
影响因子：
3.8
通讯作者：
Glazer RI
中科院分区：
文献类型：
--
作者：
Xie Z;Yuan H;Yin Y;Zeng X;Bai R;Glazer RI
转移是乳腺癌发病和死亡的主要原因，肿瘤细胞的侵袭在转移过程中起着至关重要的作用。PDK 1是一种关键分子，其响应于生长因子受体活化将PI 3 K与细胞增殖和存活信号偶联，并且当在小鼠乳腺上皮细胞中表达时是致癌的。我们现在提出的证据表明，PDK 1表达细胞表现出增强的锚定依赖性和非依赖性细胞生长，并高度侵入性时，生长在基质胶。这些特性与MMP-2活性的诱导、MT 1-MMP表达的增加和独特的基因表达谱相关。采用Matrigel侵袭试验、MMP-2酶谱分析、基因微阵列分析和乳腺同种移植物来表征表达PDK 1的细胞的侵袭和增殖功能。人乳腺癌的组织微阵列分析用于通过IHC测量侵袭性肿瘤中的PDK 1表达。PDK 1表达细胞对基质胶的侵袭增强伴随着MMP-2活性的增加，这是由于对蛋白酶体降解的稳定性。MMP-2活性的增加伴随着MT 1-MMP水平的升高，MT 1-MMP参与产生活性MMP-2。基因微阵列分析发现ECM相关基因核心蛋白聚糖和I型前胶原的表达增加，其基因产物是MT 1-MMP的底物。PDK 1表达细胞的乳腺脂肪垫同种移植物产生浸润性腺癌。人浸润性乳腺癌的组织芯片分析表明，PDK 1 pSer 241在90%的样本中强烈表达。这些结果表明，PDK 1作为一个重要的效应乳腺上皮细胞的生长和侵袭的转化表型。PDK 1部分通过MT 1-MMP诱导介导其作用，MT 1-MMP诱导又激活MMP-2并调节ECM蛋白核心蛋白聚糖和胶原。大多数浸润性乳腺癌中PDK 1表达增加的存在表明其在转移过程中的重要性。
Metastasis is a major cause of morbidity and mortality in breast cancer with tumor cell invasion playing a crucial role in the metastatic process. PDK1 is a key molecule that couples PI3K to cell proliferation and survival signals in response to growth factor receptor activation, and is oncogenic when expressed in mouse mammary epithelial cells. We now present evidence showing that PDK1-expressing cells exhibit enhanced anchorage-dependent and -independent cell growth and are highly invasive when grown on Matrigel. These properties correlate with induction of MMP-2 activity, increased MT1-MMP expression and a unique gene expression profile. Invasion assays in Matrigel, MMP-2 zymogram analysis, gene microarray analysis and mammary isografts were used to characterize the invasive and proliferative function of cells expressing PDK1. Tissue microarray analysis of human breast cancers was used to measure PDK1 expression in invasive tumors by IHC. Enhanced invasion on Matrigel in PDK1-expressing cells was accompanied by increased MMP-2 activity resulting from stabilization against proteasomal degradation. Increased MMP-2 activity was accompanied by elevated levels of MT1-MMP, which is involved in generating active MMP-2. Gene microarray analysis identified increased expression of the ECM-associated genes decorin and type I procollagen, whose gene products are substrates of MT1-MMP. Mammary fat pad isografts of PDK1-expressing cells produced invasive adenocarcinomas. Tissue microarray analysis of human invasive breast cancer indicated that PDK1pSer241 was strongly expressed in 90% of samples. These results indicate that PDK1 serves as an important effector of mammary epithelial cell growth and invasion in the transformed phenotype. PDK1 mediates its effect in part by MT1-MMP induction, which in turn activates MMP-2 and modulates the ECM proteins decorin and collagen. The presence of increased PDK1 expression in the majority of invasive breast cancers suggests its importance in the metastatic process.
登录
查看更多内容
影响因子：
11.2
作者：
Li, YY;Aoki, T;Sato, H
通讯作者：
Sato, H
DOI：
10.1073/pnas.95.25.14950
发表时间：
1998-12-08
影响因子：
11.1
作者：
Aoki, M;Batista, O;Vogt, PK
通讯作者：
Vogt, PK
影响因子：
5
作者：
Kluger, HM;Kluger, Y;Sapi, E
通讯作者：
Sapi, E
影响因子：
9.2
作者：
Belham, C;Wu, SL;Avruch, J
通讯作者：
Avruch, J
影响因子：
4.8
作者：
Ohuchi, E;Imai, K;Okada, Y
通讯作者：
Okada, Y