Phosphatidylethanolamine-binding protein 4 is associated with breast cancer metastasis through Src-mediated Akt tyrosine phosphorylation
Phosphatidylethanolamine-binding protein 4 is associated with breast cancer metastasis through Src-mediated Akt tyrosine phosphorylation
复制标题
磷脂酰乙醇胺结合蛋白 4 通过 Src 介导的 Akt 酪氨酸磷酸化与乳腺癌转移相关
DOI：
10.1038/onc.2013.408
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发表时间：
2014-09-11
期刊：
影响因子：
8
通讯作者：
Wang, X.
中科院分区：
文献类型：
--
作者：
Li, H.;Huang, F.;Wang, X.
在乳腺癌患者中观察到的死亡率中，转移占90%以上。人磷脂酰乙醇胺结合蛋白4（Human phosphatidyethanolamine-binding protein 4，hPEBP 4）是PEBP家族的一个新成员，具有抗凋亡的功能。在此，我们发现转移性MDA-MB-231乳腺癌细胞比非转移性MCF-7乳腺癌细胞表达更高水平的hPEBP 4，并且hPEBP 4的表达水平与临床乳腺癌的转移正相关。hPEBP 4在MDA-MB-231细胞中的过表达在体外显著促进细胞侵袭，在体内显著增加淋巴结转移的发展。相反，hPEBP 4的沉默抑制细胞的侵袭能力在体外和体内。进一步的研究表明，hPEBP 4促进转移相关蛋白酶MMP（基质金属蛋白酶）2、MMP 9和MMP 13的表达或活性。这种hPEBP 4增强的细胞侵袭和MMP表达是由于Akt活化的增加。Akt的敲低恢复了hPEBP 4-MDA-MB-231异种移植小鼠模型中hPEBP 4诱导的乳腺肿瘤转移。此外，我们发现，hPEBP 4作为一个支架分子，并增强协会的Akt与Src促进Akt酪氨酸磷酸化，Akt的完全激活的先决条件，在磷脂酰乙醇胺结合域依赖性的方式。鉴于目前关于人乳腺癌的信息，这些来自细胞培养和动物研究的功能数据表明，在人乳腺癌中，hPEBP 4是一种新的和临床相关的转移加速基因，并且可能是乳腺癌转移的新的诊断标志物和治疗靶点。
Metastasis is responsible for more than 90% of the mortality observed among patients with breast cancer. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of the PEBP family and functions as an anti-apoptotic molecule. Here, we found that the metastatic MDA-MB-231 breast cancer cells expressed much higher levels of hPEBP4 than the nonmetastatic MCF-7 breast cancer cells and that the expression levels of hPEBP4 were positively correlated with the metastasis of clinical breast cancer. The hPEBP4 overexpression in the MDA-MB-231 cells significantly promoted cell invasion in vitro and increased the development of lymph node metastasis in vivo. Conversely, the silencing of hPEBP4 suppressed the cell-invasive ability both in vitro and in vivo. Further investigation showed that hPEBP4 promoted the expression or activity of the metastasis-related proteinases MMP (matrix metalloproteinase) 2, MMP9 and MMP13. This hPEBP4-potentiated cell invasion and MMP expression is due to an increase in Akt activation. Knockdown of Akt restored hPEBP4-induced breast tumor metastasis in the hPEBP4-MDA-MB-231 xenograft mouse model. Moreover, we found that hPEBP4 functioned as a scaffolding molecule and enhanced the association of Akt with Src to promote Akt tyrosine phosphorylation, a prerequisite for the full activation of Akt, in a phosphatidylethanolamine-binding domain-dependent manner. Given the present information about human breast cancer, these functional data from cell culture and animal studies suggest that, in human breast cancer hPEBP4 is a novel and clinically relevant metastasis accelerator gene and may be a new diagnostic marker and therapeutic target for breast cancer metastasis.