Division of Cancer Pathobiology, Department of Pathology & Laboratory Medicine, The Children's Hospital of Philadelphia, PA 19104-4399, USA.
Oncogene. 2011 Jun 2;30(22):2587-94. doi: 10.1038/onc.2010.634. Epub 2011 Feb 7.
Downregulation of microRNA-34a by Myc is known to be essential for tumorigenesis and improve tumor-cell survival. Conversely, upregulation of miR-34a by p53 is thought to enhance its acetylation and activity and contribute to the pro-apoptotic effects of this tumor suppressor. We sought to determine whether restoration of miR-34a levels in B-lymphoid cells with Myc overexpression would aid therapeutic apoptosis. Unexpectedly, delivery of miR-34a, which doesn't target p53 directly, severely compromised steady-state p53 levels. This effect was preceded and mediated by direct targeting of Myc, which sustained p53 protein levels via the Arf-Hdm2 pathway. As a result, in the presence of Myc, miR-34a inhibited p53-dependent bortezomib-induced apoptosis as efficiently as anti-p53 small interfering RNA. Conversely, inhibition of miR-34a using antisense RNA sensitized lymphoma cells to therapeutic apoptosis. Thus, in tumors with deregulated Myc expression, miR-34a confers drug resistance and could be considered a therapeutic target.
Myc 下调 microRNA-34a 已知对肿瘤发生和改善肿瘤细胞存活至关重要。相反，p53 上调 miR-34a 被认为可以增强其乙酰化和活性，并有助于这种肿瘤抑制因子的促凋亡作用。我们试图确定在 Myc 过表达的 B 淋巴细胞中恢复 miR-34a 水平是否有助于治疗性细胞凋亡。出乎意料的是，miR-34a 的递送（其并不直接靶向 p53）严重损害了 p53 的稳态水平。这种效应以前是由 Myc 的直接靶向介导的，Myc 通过 Arf-Hdm2 途径维持 p53 蛋白水平。结果，在 Myc 存在的情况下，miR-34a 抑制了依赖于 p53 的硼替佐米诱导的细胞凋亡，与抗 p53 小干扰 RNA 一样有效。相反，使用反义 RNA 抑制 miR-34a 使淋巴瘤细胞对治疗性细胞凋亡敏感。因此，在 Myc 表达失调的肿瘤中，miR-34a 赋予了药物耐药性，可被视为治疗靶点。
