Expression of Cox-2 in human breast cancer cells as a critical determinant of epithelial-to-mesenchymal transition and invasiveness
Expression of Cox-2 in human breast cancer cells as a critical determinant of epithelial-to-mesenchymal transition and invasiveness
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DOI：
10.1517/14728222.2014.860447
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发表时间：
2014-02-01
影响因子：
5.8
通讯作者：
Miglietta, Antonella
中科院分区：
文献类型：
--
作者：
Bocca, Claudia;Ievolella, Monica;Miglietta, Antonella
简介：环氧合酶-2（考克斯-2）在几种恶性肿瘤中过表达，并与乳腺癌的进展有关。Objectives：我们研究了考克斯-2表达的变化是否可能影响上皮细胞向间质细胞转化（EMT），然后影响人乳腺癌细胞的侵袭潜力，与缺氧的关系。结果：考克斯-2过表达导致E-cadherin、β-catenin表达下调，vimentin、N-cadherin和SNAI 1表达上调，提示EMT的发生。考克斯-2过表达的MCF-7细胞的特征还在于增加的侵袭性和基质金属蛋白酶-9的释放。上述特征与在高侵袭性MDA-MB-231细胞中检测到的特征相似，通过用塞来昔布（一种考克斯-2特异性抑制剂）处理过表达考克斯-2的MCF-7细胞，部分通过抑制与考克斯-2相关的细胞内活性氧簇的产生而逆转。缺氧可进一步促进考克斯-2高表达的MCF-7细胞和MDA-MB-231细胞中考克斯-2的表达、EMT改变和侵袭能力。最后，对正常和肿瘤性人类乳腺组织样本进行的免疫组织化学显示，考克斯-2阳性恶性细胞也对EMT相关抗原、缺氧诱导因子（HIF）-2 α和氧化应激标志物血红素加氧酶呈阳性。这些发现支持考克斯-2过表达、EMT和人乳腺癌细胞侵袭性之间存在直接联系，强调缺氧微环境的作用。
Introduction: Cyclooxygenase-2 (COX-2) is overexpressed in several malignancies and is implicated in breast cancer progression.Objectives: We investigated whether changes in COX-2 expression may affect epithelial-to-mesenchymal transition (EMT) and then invasive potential of human breast cancer cells, in relationship with hypoxia. COX-2-null MCF-7 human breast cancer cells, MCF-7 cells transiently expressing COX-2 and COX-2-expressing MDA-MB-231 cells were employed.Results: COX-2 overexpression resulted in downregulation of E-cadherin and beta-catenin, upregulation of vimentin, N-cadherin and SNAI1, suggesting EMT occurrence. COX-2-overexpressing MCF-7 cells were also characterized by increased invasiveness and release of matrix-metalloproteinase-9. The above-mentioned characteristics, homologous to those detected in highly invasive MDA-MB-231 cells, were reverted by treatment of COX-2-overexpressing MCF-7 cells with celecoxib, a COX-2-specific inhibitor, partly through the inhibition of COX-2-related intracellular generation of reactive oxygen species. Hypoxia further exacerbated COX-2 expression, EMT changes and invasive ability in both COX-2-overexpressing MCF-7 cells and MDA-MB-231 cells. Finally, immunohistochemistry performed on samples from normal and neoplastic human breast tissues revealed that COX-2-positive malignant cells were also positive for EMT-related antigens, hypoxia-inducible factor (HIF)-2 alpha and the oxidative stress marker heme oxygenase.Conclusions: These findings support the existence of a direct link between COX-2 overexpression, EMT and invasiveness in human breast cancer cells, emphasizing the role of hypoxic microenvironment.