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微小RNA-146a通过激活Notch信号通路促进黑色素瘤的发生和发展。

miR-146a promotes the initiation and progression of melanoma by activating Notch signaling.

作者信息

Forloni Matteo, Dogra Shaillay Kumar, Dong Yuying, Conte Darryl, Ou Jianhong, Zhu Lihua Julie, Deng April, Mahalingam Meera, Green Michael R, Wajapeyee Narendra

机构信息

Department of Pathology, Yale University School of Medicine, New Haven, United States.

出版信息

Elife. 2014 Feb 18;3:e01460. doi: 10.7554/eLife.01460.

DOI:10.7554/eLife.01460
PMID:24550252
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3927633/
Abstract

Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. In this study, we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma. DOI: http://dx.doi.org/10.7554/eLife.01460.001.

摘要

BRAF和NRAS中的致癌突变存在于70%的黑色素瘤中。在本研究中，我们鉴定出一种微小RNA，即miR-146a，它被致癌性BRAF和NRAS高度上调。miR-146a的表达增强了人类黑色素瘤细胞在培养物中增殖以及在小鼠体内形成肿瘤的能力，而敲低miR-146a则产生相反的效果。我们表明这些致癌活性是由于miR-146a靶向NUMB mRNA，一种Notch信号通路的抑制因子。先前的研究表明前体miR-146a包含一个单核苷酸多态性（C>G rs2910164）。我们发现前体miR-146a/G激活Notch信号通路并促进肿瘤发生的能力显著高于前体miR-146a/C。对黑色素瘤细胞系和匹配的患者样本的分析表明，在黑色素瘤进展过程中，相对于前体miR-146a/C，前体miR-146a/G富集，这是由前体miR-146a/C中的C到G体细胞突变导致的。总体而言，我们的结果揭示了miR-146a在黑色素瘤起始和进展中的核心作用。DOI: http://dx.doi.org/10.7554/eLife.01460.001。

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