A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors
A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors
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DOI：
10.1016/j.cell.2006.02.037
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发表时间：
2006-03-24
期刊：
影响因子：
64.5
通讯作者：
Agami, R
中科院分区：
文献类型：
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作者：
Voorhoeve, PM;le Sage, C;Agami, R
内源性小 RNA (miRNA) 通过后生动物中保守的机制调节基因表达。虽然经过验证的人类 miRNA 的数量仍在增加，但只有很少的 miRNA 得到了功能注释。为了对 miRNA 的新功能进行遗传筛选，我们开发了一个表达大多数克隆人类 miRNA 的载体库，并创建了相应的 DNA 条形码阵列。在筛选细胞转化中与癌基因配合的 miRNA 时，我们鉴定了 miR-372 和 miR-373，它们各自允许同时含有致癌 RAS 和活性野生型 p53 的原代人类细胞增殖和肿瘤发生。这些 miRNA 可能通过直接抑制肿瘤抑制因子 LATS2 的表达来中和 p53 介导的 CDK 抑制。我们提供的证据表明，这些 miRNA 是潜在的新型致癌基因，通过麻木 p53 通路参与人类睾丸生殖细胞肿瘤的发展，从而在野生型 p53 存在的情况下允许肿瘤生长。
Endogenous small RNAs (miRNAs) regulate gene expression by mechanisms conserved across metazoans. While the number of verified human miRNAs is still expanding, only few have been functionally annotated. To perform genetic screens for novel functions of miRNAs, we developed a library of vectors expressing the majority of cloned human miRNAs and created corresponding DNA barcode arrays. In a screen for miRNAs that cooperate with oncogenes in cellular transformation, we identified miR-372 and miR-373, each permitting proliferation and tumorigenesis of primary human cells that harbor both oncogenic RAS and active wild-type p53. These miRNAs neutralize p53-mediated CDK inhibition, possibly through direct inhibition of the expression of the tumor-suppressor LATS2. We provide evidence that these miRNAs are potential novel oncogenes participating in the development of human testicular germ cell tumors by numbing the p53 pathway, thus allowing tumorigenic growth in the presence of wild-type p53.