Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Oncogene. 2010 May 6;29(18):2638-48. doi: 10.1038/onc.2010.23. Epub 2010 Feb 15.
Cancer cells show characteristic gene expression profiles. Recent studies support the potential importance of microRNA (miRNA) expression signatures as biomarkers and therapeutic targets. The membrane-anchored protease regulator RECK is downregulated in many cancers, and forced expression of RECK in tumor cells results in decreased malignancy in animal models. RECK is also essential for mammalian development. In this study, we found that RECK is a target of at least three groups of miRNAs (miR-15b/16, miR-21 and miR-372/373); that RECK mutants lacking the target sites for these miRNA show augmented tumor/metastasis-suppressor activities; and that miR-372/373 are upregulated in response to hypoxia through HIF1alpha and TWIST1, whereas miR-21 is upregulated by RAS/ERK signaling. These data indicate that the hypoxia- and RAS-signaling pathways converge on RECK through miRNAs, cooperatively downregulating this tumor suppressor and thereby promoting malignant cell behavior.
癌细胞表现出特征性的基因表达谱。最近的研究支持 miRNA（miRNA）表达特征作为生物标志物和治疗靶点的潜在重要性。膜锚定蛋白酶调节剂 RECK 在许多癌症中下调，并且在肿瘤细胞中强制表达 RECK 会导致动物模型中恶性程度降低。RECK 对哺乳动物的发育也是必不可少的。在这项研究中，我们发现 RECK 是至少三组 miRNA（miR-15b/16、miR-21 和 miR-372/373）的靶标；缺乏这些 miRNA 靶位点的 RECK 突变体显示出增强的肿瘤/转移抑制活性；并且 miR-372/373 通过 HIF1alpha 和 TWIST1 响应缺氧而上调，而 miR-21 则通过 RAS/ERK 信号上调。这些数据表明，缺氧和 RAS 信号通路通过 miRNA 汇聚在 RECK 上，协同地下调这种肿瘤抑制因子，从而促进恶性细胞行为。
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