Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad Miguel Hernández (UMH), Campus de Sant Joan, Sant Joan, Alicante, Spain.
EMBO J. 2011 Feb 16;30(4):756-69. doi: 10.1038/emboj.2010.358. Epub 2011 Jan 11.
Notch signalling is crucial for the correct development and growth of numerous organs and tissues, and when subverted it can cause cancer. Loss of miR-8/200 microRNAs (miRNAs) is commonly observed in advanced tumours and correlates with their invasion and acquisition of stem-like properties. Here, we show that this miRNA family controls Notch signalling activation in Drosophila and human cells. In an overexpression screen, we identified the Drosophila miR-8 as a potent inhibitor of Notch-induced overgrowth and tumour metastasis. Gain and loss of mir-8 provoked developmental defects reminiscent of impaired Notch signalling and we demonstrated that miR-8 directly inhibits Notch ligand Serrate. Likewise, miR-200c and miR-141 directly inhibited JAGGED1, impeding proliferation of human metastatic prostate cancer cells. It has been suggested that JAGGED1 may also be important for metastases. Although in metastatic cancer cells, JAGGED1 modestly regulated ZEB1, the miR-200c's target in invasion, studies in Drosophila revealed that only concurrent overexpression of Notch and Zfh1/ZEB1 induced tumour metastases. Together, these data define a new way to attenuate or boost Notch signalling that may have clinical interest.
Notch 信号通路对于许多器官和组织的正常发育和生长至关重要，而当其发生异常时则可能导致癌症。miR-8/200 微 RNA（miRNA）家族的缺失在晚期肿瘤中较为常见，并且与肿瘤的侵袭和干性获得相关。本研究显示，该 miRNA 家族可调控果蝇和人细胞中的 Notch 信号通路激活。在过表达筛选中，我们发现果蝇 miR-8 可强力抑制 Notch 诱导的过度生长和肿瘤转移。miR-8 的过表达和缺失可引发类似于 Notch 信号通路缺陷的发育缺陷，并且我们证实 miR-8 可直接抑制 Notch 配体 Serrate。类似地，miR-200c 和 miR-141 可直接抑制 JAGGED1，从而抑制人转移性前列腺癌细胞的增殖。已有研究表明，JAGGED1 对于转移可能也很重要。尽管在转移性癌细胞中，JAGGED1 可适度调控侵袭相关的 miR-200c 靶基因 ZEB1，但在果蝇中的研究显示，只有 Notch 和 Zfh1/ZEB1 的协同过表达才会诱导肿瘤转移。综上，这些数据定义了一种新的减弱或增强 Notch 信号通路的方法，可能具有临床意义。
