Interaction of the oncogenic miR-21 microRNA and the p53 tumor suppressor pathway
Interaction of the oncogenic miR-21 microRNA and the p53 tumor suppressor pathway
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致癌 miR-21 microRNA 与 p53 肿瘤抑制通路的相互作用
DOI：
10.1093/carcin/bgt044
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发表时间：
2013-06-01
期刊：
影响因子：
4.7
通讯作者：
Li, Yong
中科院分区：
文献类型：
--
作者：
Ma, Xiaodong;Choudhury, Saibyasachi N.;Li, Yong
MicroRNA-21(miR-21)在几乎所有人类癌症中都过表达，并在转基因小鼠模型中显示出致癌活性。同样，P53抑癌基因是人类癌症中最常见的突变基因，其缺失或突变会导致小鼠肿瘤形成。为了确定miR-21在体内p53途径中的作用并研究它们在肿瘤发生中的相互作用，我们将miR-21(/)和Trp53(/)小鼠进行了杂交。我们发现TrP53(/)miR-21(/)小鼠出现肿瘤的年龄稍晚，但表现出与TrP53(/)小鼠相似的肿瘤谱和生存曲线。Trp53(/)miR-21(/)小鼠的组织在受到基因毒性药物作用时，其组织中有较高比例的凋亡细胞。我们提取了小鼠胚胎成纤维细胞(MEF)，以检测miR-21缺失对TrP53(/)细胞中P53调控的细胞过程的影响。Trp53(/)miR-21(/)MEF较TrP53(/)MEF具有更高的细胞凋亡率和细胞衰退率。此外，miR-21的缺失通过上调Pten的表达使转化的Trp53(/)细胞对DNA损伤诱导的细胞凋亡变得敏感。这些数据表明，抑制miR-21将有益于针对p53缺失肿瘤的凋亡诱导癌症治疗。
MicroRNA-21 (miR-21) is overexpressed virtually in all human cancers and displays oncogenic activity in a transgenic murine model. Similarly, the p53 tumor suppressor gene is the most frequently mutated gene in human cancer, and its loss or mutation leads to tumor formation in mice. To ascertain the role of miR-21 in the p53 pathway in vivo and to characterize their interaction in tumorigenesis, we intercrossed the miR-21(/) and Trp53(/) mice. We found that Trp53(/)miR-21(/)mice develop tumors at a slightly later age, yet show a similar tumor spectrum and survival curve as Trp53(/) mice. When subjected to genotoxic agents, tissues from Trp53(/)miR-21(/) mice have a higher percentage of apoptotic cells. We extracted mouse embryonic fibroblast cells (MEFs) to examine the impact of miR-21 loss on p53-regulated cellular processes in Trp53(/) cells. Higher cellular apoptosis and senescence were found in Trp53(/)miR-21(/) MEFs than in Trp53(/) MEFs. In addition, loss of miR-21 sensitizes transformed Trp53(/) cells to DNA damage-induced apoptosis through elevation of Pten expression. These data suggest that inhibition of miR-21 would be beneficial in apoptosis-inducing cancer therapies directed against p53-deficient tumors.