MnSOD up-regulates maspin tumor suppressor gene expression in human breast and prostate cancer cells
MnSOD up-regulates maspin tumor suppressor gene expression in human breast and prostate cancer cells
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DOI：
10.1089/152308603770310356
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发表时间：
2003-10-01
影响因子：
6.6
通讯作者：
Domann, FE
中科院分区：
文献类型：
--
作者：
Duan, H;Zhang, HJ;Domann, FE
锰超氧化物歧化酶（MnSOD）是一种具有肿瘤抑制活性的抗氧化酶；然而，MnSOD抗肿瘤作用的分子机制尚不清楚。我们假设癌细胞中的MnSOD活性可能导致下游其他肿瘤抑制基因表达的变化。为了确定maspin（一种抑制乳腺癌细胞侵袭和转移的肿瘤抑制基因）是否可能是MnSOD的靶点，我们通过腺病毒介导的基因转移在几种人乳腺癌和前列腺癌细胞系中强迫MnSOD表达，并测量了maspin mRNA的表达。MnSOD的强制表达导致maspin mRNA在人乳腺癌和前列腺癌细胞中以剂量依赖的方式积累。正常p53不需要介导MnSOD的作用，因为MnSOD在携带野生型p53的细胞和携带突变型p53的细胞中上调了maspin。此外，MnSOD对masmasin的作用不是由于masmasin启动子的去甲基化。对maspin启动子活性、转录运行和mRNA稳定性的分析表明，maspin mRNA稳定性是MnSOD上调maspin的主要机制。我们的研究结果确定了MnSOD抗肿瘤作用的机制，并为MnSOD作为一种基因疗法治疗人类乳腺癌和前列腺癌提供了证据。
Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme with tumor suppressor activity; however, the molecular mechanisms of MnSOD antitumor effects remain unclear. We hypothesized that MnSOD activity in cancer cells might cause downstream changes in the expression of other tumor suppressor genes. To determine whether maspin, a tumor suppressor gene that inhibits breast cancer cell invasion and metastasis, might be a target of MnSOD, we forced MnSOD expression in several human breast and prostate cancer cell lines by adenovirus-mediated gene transfer and measured maspin mRNA expression. Forced expression of MnSOD caused maspin mRNA to accumulate in a dose-dependent manner in both human breast and prostate cancer cells. Normal p53 was not necessary to mediate the effect of MnSOD because MnSOD up-regulated maspin in cells that harbor wild-type p53 and in cells that harbor mutant p53. Moreover, the effects of MnSOD on maspin were not due to demethylation of the maspin promoter. Analyses of maspin promoter activity, transcriptional run-on, and mRNA stability showed that maspin mRNA stability was the major mechanism for maspin up-regulation by MnSOD. Our findings identify a mechanism underlying MnSOD antitumor effects and provide evidence to support MnSOD as a genetic therapy in the treatment of human breast and prostate cancers.