MDM2 Promotes Invasion and Metastasis in Invasive Ductal Breast Carcinoma by Inducing Matrix Metalloproteinase-9
MDM2 Promotes Invasion and Metastasis in Invasive Ductal Breast Carcinoma by Inducing Matrix Metalloproteinase-9
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MDM2通过诱导基质金属蛋白酶9促进浸润性导管乳腺癌的侵袭和转移
DOI：
10.1371/journal.pone.0078794
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发表时间：
2013-11-13
期刊：
影响因子：
3.7
通讯作者：
Yin, Yongmei
中科院分区：
文献类型：
--
作者：
Chen, Xiaofeng;Qiu, Jinrong;Yin, Yongmei
浸润性导管性乳腺癌（IDC）侵袭和转移的分子机制尚不完全清楚。致癌基因小鼠双分钟2 （MDM2）与许多癌症的发病机制有关，它刺激基质金属蛋白酶9 （MMP9）的表达，MMP9是细胞外基质分解的重要酶。然而，它在乳腺癌中的作用仍然知之甚少。本研究评估MDM2在IDC中表达的临床意义，并采用体外表达法确定MDM2的分子作用。对2002年1月至2003年12月在中国南京医科大学第一附属医院因IDC手术切除的321名妇女的肿瘤块进行MMP9和MDM2的免疫组化染色。用靶向MDM2的siRNA转染MCF-7和MDA-MD-231细胞系，或用瞬时表达载体过表达MDM2。然后评估MDM2过表达或过表达的细胞的侵袭、细胞迁移和蛋白水解能力，并与对照细胞进行比较，以及使用RT-PCR对MMP9表达的影响。体内MMP9和MDM2分别有54.9%和49.6%的样本呈阳性表达，两者表达呈显著相关（r2 = 0.171, P = 0.012）。此外，MDM2表达与无病生存率显著相关（HR 2.56, 95% CI 1.02 ~ 6.40, P = 0.038）。在体外，与对照细胞相比，MDM2过表达显著增强了细胞的侵袭、迁移和蛋白水解，而在MDM2- sirna处理后，观察到相反的效应。MDM2过表达诱导MMP9表达呈剂量依赖性。综上所述，这些结果表明，高水平的MDM2与IDC患者预后较差有关。这可能是由于MMP9表达增强导致细胞外基质分解增加，从而增加了肿瘤的侵袭性。
The molecular mechanisms that underpin invasive ductal breast cancer (IDC) invasion and metastasis are incompletely understood. The oncogene, mouse double minute 2 (MDM2), has been implicated in the pathogenesis of numerous cancers, where it stimulates the expression of matrix metalloproteinase 9 (MMP9), an important enzyme in the breakdown of the extracellular matrix. However, its role in breast cancer remains poorly understood. This study assessed the clinical significance of MDM2 expression in IDC and used in vitro expression assays to determine the molecular roles of MDM2. Immunohistochemical staining for MMP9 and MDM2 was performed using archived tumor blocks from 321 women who underwent surgical resection for IDC at the First Affiliated Hospital of Nanjing Medical University, China between January 2002 and December 2003. MCF-7 and MDA-MD-231 cell lines were transfected with siRNA targeted against MDM2, or MDM2 was overexpressed using transiently expressed vectors. The invasion, cell migration and proteolytic capabilities of cells that over- or underexpressed MDM2 was then assessed and compared against control cells, in addition to the consequent effects on MMP9 expression using RT-PCR. In vivo, 54.9% and 49.6% of samples were positive for MMP9 and MDM2 expression, respectively, and their expression was significantly correlated (r2 = 0.171, P = 0.012). Moreover, MDM2 expression was markedly correlated with disease-free survival (HR 2.56, 95% CI 1.02–6.40, P = 0.038). In vitro, MDM2 overexpression significantly enhanced cell invasion, migration and proteolysis compared with control cells, and the converse effects were observed after MDM2-siRNA treatment. MDM2 overexpression induced MMP9 expression in a dose-dependent manner. Taken together, these results suggest that high levels of MDM2 are associated with a poorer prognosis in IDC. This might result from increased tumor invasiveness due to enhanced MMP9 expression causing increased extracellular matrix breakdown.