Herne oxygenase-1 inhibits breast cancer invasion via suppressing the expression of matrix metalloproteinase-9
Herne oxygenase-1 inhibits breast cancer invasion via suppressing the expression of matrix metalloproteinase-9
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DOI：
10.1158/1535-7163.mct-07-2199
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发表时间：
2008-05-01
影响因子：
5.7
通讯作者：
Chen, Yen-Chou
中科院分区：
文献类型：
--
作者：
Lin, Cheng-Wei;Shen, Shing-Chun;Chen, Yen-Chou
在本研究中，我们研究了血红素加氧酶1（HO-1）在人乳腺癌细胞中的侵袭和迁移的抗肿瘤作用。在人乳腺癌细胞（MCF-7和MDA-MB-231）中检测了12-O-十四酰佛波醇-13-乙酸酯（TPA）诱导的基质金属蛋白酶-9（MMP-9）酶活性和蛋白质和mRNA水平的基因表达，并且根据体外Transwell测定，MMP-9抑制剂SB 3CT的加入显著抑制TPA诱导的侵袭和迁移。铁原卟啉IX升高HO-1基因表达抑制TPA诱导的MCF-7细胞侵袭，加入血红素加氧酶抑制剂，锡原卟啉IX，或转染细胞与HO-1短发夹RNA阻断。本研究建立了过表达HO-1的MCF-7细胞（MCF-7/HO-1），与Neo转染细胞相比，TPA诱导的MCF-7/HO-1细胞MMP-9基因表达、肿瘤侵袭和集落形成均显著降低。蛋白激酶C α/细胞外信号调节激酶/AP-1的激活与活性氧产生的刺激参与TPA诱导的MCF-7细胞的侵袭，其被铁原卟啉IX诱导的HO-1蛋白或转染HO-1表达载体所减弱。此外，添加一氧化碳，而不是铁离子，胆绿素，或胆红素，抑制TPA诱导的侵袭，通过抑制MMP-9，细胞外信号调节激酶，和AP-1激活刺激TPA。HO-1在阻断肿瘤侵袭中的有益作用在本研究中首次被确定。
In the present study, we investigated the antitumor effects of the invasiveness and migration of heme oxygenase 1 (HO-1) in human breast carcinoma cells. 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-9 (MMP-9) enzyme activity and gene expression at both protein and mRNA levels were examined in human breast carcinoma cells (MCF-7 and MDA-MB-231), and the addition of the MMP-9 inhibitor, SB3CT, significantly suppressed TPA-induced invasion and migration according to the in vitro Transwell assay. Elevation of HO-1 gene expression by ferric protoporphyrin IX inhibited TPA-induced invasion of MCF-7 cells, which was blocked by adding the heme oxygenase inhibitor, tin protoporphyrin IX, or transfection of cells with HO-1 short hairpin RNA. MCF-7 cells overexpressing HO-1 (MCF-7/HO-1) were established in the present study, and TPA-induced MMP-9 gene expression, tumor invasion, and colony formation were significantly reduced in MCF-7/HO-1 cells, compared with those in Neo-transfected cells. Activation of protein kinase C alpha/extracellular signal-regulated kinases/AP-1 with stimulation of reactive oxygen species production was involved in TPA-induced invasion of MCF-7 cells, which was attenuated by HO-1 protein induced by ferric protoporphyrin IX or transfection of HO-1 expression vectors. Additionally, the addition of carbon monoxide, but not ferric ions, biliverdin, or bilirubin, inhibited TPA-induced invasion through suppressing MMP-9, extracellular signal-regulated kinases, and AP-1 activation stimulated by TPA. The beneficial role of HO-1 in blocking tumor invasion was first identified in this study.