Overexpression of MMP-9 and HIF-1α in Breast Cancer Cells under Hypoxic Conditions.
Overexpression of MMP-9 and HIF-1α in Breast Cancer Cells under Hypoxic Conditions.
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DOI：
10.4048/jbc.2011.14.2.88
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发表时间：
2011-06
影响因子：
2.4
通讯作者：
Song JY
中科院分区：
文献类型：
--
作者：
Choi JY;Jang YS;Min SY;Song JY
缺氧是组织中氧气的损失，是实体瘤中常见的情况，因为肿瘤超出了现有的血管系统。在缺氧条件下，缺氧诱导因子(HIF)-1α迅速积累并激活数百个基因，如基质金属蛋白酶（MMPs）。MMPs通过降解周围基底膜和细胞外基质屏障，促进肿瘤细胞的侵袭和转移，使癌细胞易于迁移和扩散。我们研究了缺氧是否会增加肿瘤细胞的侵袭，以及侵袭性的增加是否与HIF-1α和MMP-9的表达有关。利用MDA-MB-231乳腺癌细胞进行Transwell侵袭试验，以证明缺氧是否会增强肿瘤的侵袭。免疫荧光法检测缺氧条件下HIF-1α和MMP-9的表达。荧光素酶和ChiP实验证实MMP-9启动子活性受HIF-1α调控。HIF-1α在缺氧条件下稳定，刺激MMP-9的表达，影响乳腺癌细胞的肿瘤侵袭性。HIF-1α通过与p300形成转录单元反激活MMP-9启动子，从而增加MMP-9转录本的表达。酶谱分析表明，MMP-9在缺氧条件下的明胶酶活性高于常氧条件。此外，小GTPase Ras也在缺氧时被激活，这有助于HIF-1α的稳定，进而上调MMP-9的表达。我们还证实MMP-9在乳腺癌患者的肿瘤组织中与HIF-1α同时上调。这些结果表明HIF-1α通过MMP-9依赖机制促进细胞侵袭，未来的抗肿瘤药物可以针对HIF-1α和MMP-9。
Hypoxia, which is a loss of oxygen in tissues, is a common condition in solid tumors due to the tumor outgrowing existing vasculature. Under hypoxic conditions, hypoxia-inducible factor (HIF)-1α rapidly accumulates and transactivates hundreds of genes, such as matrix metalloproteinases (MMPs). MMPs contribute to invasion and metastasis of tumor cells by degrading the surrounding basement membrane and extracellular matrix barriers, which enables the easy migration and spread of cancer cells. We examined whether hypoxia increases tumor cell invasion, and whether increased invasiveness was due to HIF-1α and MMP-9 expression. Transwell invasion assays were performed to demonstrate whether hypoxia enhance tumor invasion by use of MDA-MB-231 breast cancer cells. An immunofluorescence assay was used to demonstrate expression of HIF-1α and MMP-9 under hypoxic conditions. Luciferase and ChiP assays were performed to demonstrate that MMP-9 promoter activity was regulated by HIF-1α. HIF-1α was stabilized under hypoxic conditions and stimulated MMP-9 expression, which affected the tumor invasiveness of breast cancer cells. HIF-1α transactivated the MMP-9 promoter by forming a transcriptional unit with p300, thus increasing expression of MMP-9 transcripts. Zymography indicated that MMP-9 had more gelatinase activity under hypoxic conditions than normoxic conditions. Furthermore, the small GTPase Ras was also activated in response to hypoxia, which then aids stabilization of HIF-1α, and in turn upregulates MMP-9 expression. We also demonstrate that MMP-9 is upregulated concurrently with HIF-1α in tumor tissues from patients with breast cancer. These results suggest that HIF-1α promotes cell invasion through a MMP-9-dependent mechanism and that future antitumor agents could be used to target HIF-1α and MMP-9.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
11.5
作者：
Giatromanolaki, A;Koukourakis, MI;Sivridis, E
通讯作者：
Sivridis, E
DOI：
10.1186/bcr813
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Bos R;van Diest PJ;van der Groep P;Shvarts A;Greijer AE;van der Wall E
通讯作者：
van der Wall E
影响因子：
3.9
作者：
Jensen, Randy L.;Ragel, Brian T.;Gillespie, David
通讯作者：
Gillespie, David
影响因子：
56.9
作者：
Ivan, M;Kondo, K;Kaelin, WG
通讯作者：
Kaelin, WG