Elevated sod2 activity augments matrix metalloproteinase expression: evidence for the involvement of endogenous hydrogen peroxide in regulating metastasis.
Elevated sod2 activity augments matrix metalloproteinase expression: evidence for the involvement of endogenous hydrogen peroxide in regulating metastasis.
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发表时间：
2003
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通讯作者：
K. Nelson;A. Ranganathan;Jelriza Mansouri;Ana M. Rodriguez;K. Providence;J. Rutter;K. Pumiglia;J. Bennett;J. Melendez
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作者：
K. Nelson;A. Ranganathan;Jelriza Mansouri;Ana M. Rodriguez;K. Providence;J. Rutter;K. Pumiglia;J. Bennett;J. Melendez
锰超氧化物歧化酶（sod 2）水平升高与某些癌症的肿瘤侵袭和转移频率增加有关，本研究的目的是研究这种情况发生的分子机制。实验设计：使用过表达Sod 2和过氧化氢酶的HT-1080纤维肉瘤细胞系，评价H2 O2对基质金属蛋白酶（MMP）-1启动子活性、丝裂原活化蛋白（MAP）激酶信号传导、DNA结合活性和MMP mRNA水平的依赖性调节。Sod 2过表达细胞的侵袭和转移潜力的特征在于分别使用肾包膜下植入或尾静脉注射肿瘤细胞到裸鼠中。结果我们的数据表明，Sod 2过表达增加了MMP表达的关键转录因子的DNA结合活性，但也通过Ras//MAP/细胞外信号调节激酶（MEK）信号级联增强MMP-1启动子活性。在-1607 bp处产生Ets位点的单核苷酸多态性赋予Sod 2依赖性MMP-1启动子活性。Sod 2过表达还增加MMPs-2、-3、-7、-10、-9、-11的mRNA水平，并且当植入免疫缺陷小鼠时增强纤维肉瘤细胞的转移潜力。AP-1和SP-1 DNA结合活性、MMP-1启动子活性、一般MMP表达和胶原降解的SOD 2依赖性增加可被过氧化氢解毒酶过氧化氢酶逆转。结论MMP在肿瘤间质浸润和转移过程中起重要作用，提示Sod 2表达增加与肿瘤预后不良有关。
PURPOSE Elevated manganese superoxide dismutase (Sod2) levels have been reported to be associated with an increased frequency of tumor invasion and metastasis in certain cancers, and the aim of this study is to examine the molecular mechanisms by which this occurs. EXPERIMENTAL DESIGN Sod2 and catalase overexpressing HT-1080 fibrosarcoma cell lines were used to evaluate the H(2)O(2)-dependent regulation of matrix metalloproteinase (MMP)-1 promoter activity, mitogen-activated protein (MAP) kinase signaling, DNA-binding activity, and MMP mRNA levels. The invasive and metastatic potential of Sod2 overexpressing cells was characterized using subrenal capsular implantation or tail vein injection of tumor cells into nude mice, respectively. RESULTS Our data reveal that Sod2 overexpression increases the DNA-binding activity of transcription factors critical for MMP expression but also enhances MMP-1 promoter activity via the Ras//MAP/extracellular signal-regulated kinase (MEK) signaling cascade. A single nucleotide polymorphism that creates an Ets site at position -1607 bp confers Sod2-dependent MMP-1 promoter activity. Sod2 overexpression also increases the mRNA levels of MMPs-2, -3, -7, -10, -9, -11 and enhances the metastatic potential of fibrosarcoma cells when implanted in immunodeficient mice. The Sod2-dependent increases in AP-1 and SP-1 DNA-binding activity, MMP-1 promoter activity, general MMP expression, and collagen degradation can be reversed by the hydrogen peroxide-detoxifying enzyme, catalase. CONCLUSION MMPs play a critical role in the process of stromal invasion and metastasis, and these findings suggest that the association between increased Sod2 and poor prognosis in certain cancers may be attributed to elevated MMP production.