PTH-related prote in upregulates integrin α6β4 expression and activates Akt in breast cancer cells
PTH-related prote in upregulates integrin α6β4 expression and activates Akt in breast cancer cells
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DOI：
10.1016/j.yexcr.2006.08.011
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发表时间：
2006-11-15
影响因子：
3.7
通讯作者：
Falzon, Miriam
中科院分区：
文献类型：
--
作者：
Shen, Xiaoli;Falzon, Miriam
乳腺癌是最常见的骨转移癌。肿瘤产生的甲状旁腺相关蛋白（PTHrP）是一种已知的骨吸收刺激因子，是乳腺癌溶骨性过程的主要介质。我们以前已经表明PTHrP增加乳腺癌细胞增殖、存活、迁移和促侵袭整合素α 6 β 4表达。为了确定整合素α 6 β 4在这些PTHrP介导的作用中的作用，我们利用两种策略来调节亲本和PTHrP过表达的MDA-MB-231和MCF-7细胞中α 6和β 4亚基的表达：通过用编码α 6和134亚基的构建体转染来过表达α 6 β 4，以及通过用靶向这些亚基的siRNA转染来抑制内源性α 6 β 4表达。我们现在表明PTHrP的作用是通过上调整合素α 6 β 4的表达来介导的。我们还表明，整合素α 6 β 4的表达在mRNA水平上进行调节，表明PTHrP的转录和/或转录后作用机制。PTHrP表达也增加了磷酸化Akt的水平，从而增加了磷酸化（无活性）糖原合成酶激酶-3（GSK-3）的水平。PTHrP在乳腺癌生长和转移中的作用可能因此通过上调整合素α 6 β 4表达和Akt活化介导，随后使GSK-3失活。(c)2006年爱思唯尔公司All rights reserved.
Breast cancer is the most common carcinoma that metastasizes to bone. Tumor-produced parathyroid hormone-related protein (PTHrP), a known stimulator of osteoclastic bone resorption, is a major mediator of the osteolytic process in breast cancer. We have previously shown that PTHrP increases breast cancer cell proliferation, survival, migration, and pro-invasive integrin alpha 6 beta 4 expression. To determine the role of integrin alpha 6 beta 4 in these PTHrPmediated effects, we utilized two strategies to modulate expression of the alpha 6 and beta 4 subunits in parental and PTHrP-overexpres sing MDA-MB-231 and MCF-7 cells: overexpression of alpha 6 beta 4 by transfection with constructs encoding the alpha 6 and 134 subunits, and suppression of endogenous alpha 6 beta 4 expression by transfection with siRNAs targeting these subunits. We now show that the effects of PTHrP are mediated via upregulation of integrin alpha 6 beta 4 expression. We also show that integrin alpha 6 beta 4 expression is modulated at the mRNA level, indicating a transcriptional and/or post-transcriptional mechanism of action for PTHrP. PTHrP expression also increased the levels of phosphorylated Akt, with a consequent increase in the levels of phosphorylated (inactive) glycogen synthase kinase-3 (GSK-3). The role of PTHrP in breast cancer growth and metastasis may thus be mediated via upregulation of integrin alpha 6 beta 4 expression and Akt activation, with consequent inactivation of GSK-3. (c) 2006 Elsevier Inc. All rights reserved.