CD147 promotes melanoma progression through hypoxia-induced MMP2 activation.
CD147 promotes melanoma progression through hypoxia-induced MMP2 activation.
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DOI：
10.2174/15665240113136660077
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发表时间：
2013-12
影响因子：
2.5
通讯作者：
W. Zeng;J. Su;L. Wu;D. Yang;T. Long;Dali Li;Y. Kuang;Jie Li;M. Qi;Jianglin Zhang;Xiang Chen
中科院分区：
文献类型：
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作者：
W. Zeng;J. Su;L. Wu;D. Yang;T. Long;Dali Li;Y. Kuang;Jie Li;M. Qi;Jianglin Zhang;Xiang Chen
缺氧增强MMP 2表达及黑色素瘤细胞的侵袭和转移能力CD147已显示在多种癌症中诱导MMP 2。为探讨CD147在低氧诱导的MMP 2活化中的作用，我们对206例正常和黑色素瘤组织进行了免疫组织化学（IHC）染色，并分析了HIF 1 α和CD147的相关性。黑色素瘤细胞系中的ChIP（chromosome Immunoprecipitation）支持HIF 1 α直接与CD 147启动子结合。此外，我们还对CD147启动子进行了一系列的缺失突变，并鉴定了一个保守的HIF 1 α结合位点。该位点的点突变显著降低了CD147对缺氧的反应。重要的是，敲低CD147减弱了黑素瘤细胞系中MMP 2对缺氧的反应。低氧不能有效激活CD147缺失细胞中的MMP 2。ELISA结果显示，缺氧条件下，CD147缺失细胞MMP 2分泌较对照组减少。为了验证细胞培养模型的数据，我们进行了体内小鼠异种移植实验。IHC染色显示，与对照组相比，CD147耗竭异种移植物中MMP 2水平降低，HIF 1 α水平相当。我们的研究证明了一个新的途径，由CD147介导的促进MMP 2激活缺氧诱导，并有助于理解缺氧和黑色素瘤的进展之间的相互作用。
Hypoxia enhances MMP2 expression and the invasion and metastatic potential of melanoma cells. CD147 has been shown to induce MMP2 in multiple cancers. To investigate the role of CD147 in hypoxiainduced MMP2 activation, we performed immunohistochemistry (IHC) staining in 206 normal and melanoma tissue samples, and analyzed the correlation between HIF1α and CD147. ChIP (chromosome Immunoprecipitation) in melanoma cell lines supports that HIF1α directly binds to CD147 promoter. Moreover, we made a series of deletion mutants of CD147 promoter, and identified a conserved HIF1α binding site. Point mutation in this site significantly decreased CD147 response to hypoxia. Importantly, knocking down CD147 attenuates MMP2 response to hypoxia in melanoma cell lines. MMP2 could not be efficiently activated by hypoxia in CD147 depletion cells. ELISA data showed that MMP2 secretion was reduced in CD147 depletion cells than control under hypoxia condition. To verify the data from cell culture model, we performed in vivo mouse xenograft experiment. IHC staining showed reduced MMP2 level in CD147 depleted xenografts compared to the control group, with the HIF1α level being comparable. Our study demonstrates a novel pathway mediated by CD147 to promote the MMP2 activation induced by hypoxia, and helps to understand the interplay between hypoxia and melanoma progression.