Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Nat Med. 2010 Oct;16(10):1134-40. doi: 10.1038/nm.2227. Epub 2010 Sep 26.
Inactivation of the p53 tumor suppressor pathway allows cell survival in times of stress and occurs in many human cancers; however, normal embryonic stem cells and some cancers such as neuroblastoma maintain wild-type human TP53 and mouse Trp53 (referred to collectively as p53 herein). Here we describe a miRNA, miR-380-5p, that represses p53 expression via a conserved sequence in the p53 3' untranslated region (UTR). miR-380-5p is highly expressed in mouse embryonic stem cells and neuroblastomas, and high expression correlates with poor outcome in neuroblastomas with neuroblastoma derived v-myc myelocytomatosis viral-related oncogene (MYCN) amplification. miR-380 overexpression cooperates with activated HRAS oncoprotein to transform primary cells, block oncogene-induced senescence and form tumors in mice. Conversely, inhibition of endogenous miR-380-5p in embryonic stem or neuroblastoma cells results in induction of p53, and extensive apoptotic cell death. In vivo delivery of a miR-380-5p antagonist decreases tumor size in an orthotopic mouse model of neuroblastoma. We demonstrate a new mechanism of p53 regulation in cancer and stem cells and uncover a potential therapeutic target for neuroblastoma.
p53 肿瘤抑制途径的失活允许细胞在应激时存活，发生在许多人类癌症中；然而，正常胚胎干细胞和一些癌症，如神经母细胞瘤，维持野生型人 TP53 和小鼠 Trp53（在此统称为 p53）。在这里，我们描述了一种 miRNA，miR-380-5p，它通过 p53 3'非翻译区（UTR）中的保守序列来抑制 p53 表达。miR-380-5p 在小鼠胚胎干细胞和神经母细胞瘤中高度表达，高表达与神经母细胞瘤中神经母细胞瘤衍生的 v-myc 髓细胞瘤病毒相关致癌基因（MYCN）扩增的不良预后相关。miR-380 过表达与激活的 HRAS 癌蛋白协同作用，转化原代细胞，阻断癌基因诱导的衰老，并在小鼠中形成肿瘤。相反，抑制胚胎干细胞或神经母细胞瘤中内源性 miR-380-5p 会诱导 p53 表达，并导致大量细胞凋亡。体内递送 miR-380-5p 拮抗剂可减少神经母细胞瘤的原位小鼠模型中的肿瘤大小。我们证明了癌症和干细胞中 p53 调节的一种新机制，并揭示了神经母细胞瘤的一个潜在治疗靶点。
