Rajabi Hasan, Jin Caining, Ahmad Rehan, McClary Cain, Joshi Maya Datt, Kufe Donald
Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02115.
Genes Cancer. 2010 Jan 1;1(1):62-68. doi: 10.1177/1947601909357933.
The MUC1 oncoprotein is overexpressed in most human breast cancers by mechanisms that are incompletely understood. The microRNA, miR-125b, is downregulated in breast cancer cells. The present studies demonstrate that the MUC1 3'UTR contains a site for binding of the miR-125b seed region. The results show that the MUC1 3'UTR suppresses luciferase expression and that this effect is abrogated by mutation or deletion of the miR-125b binding site. Expression of an anti-sense miR-125b in BT-549 breast cancer cells was associated with induction of MUC1 protein, but not MUC1 mRNA, levels. The anti-sense miR-125b also increased BT-549 cell growth by a MUC1-dependent mechanism. In addition, overexpression of exogenous miR-125b downregulated MUC1 protein, and not MUC1 transcripts, in ZR-75-1 breast cancer cells. Silencing of MUC1 in ZR-75-1 cells with a siRNA has been shown to promote DNA damage-induced apoptosis. In concert with these observations, miR-125b-induced decreases in MUC1 levels increased the apoptotic response of ZR-75-1 cells to cisplatin treatment. These findings indicate that miR-125b suppresses translation of the MUC1 oncoprotein and that miR-125b thereby functions as a tumor suppressor in breast cancer cells.
MUC1癌蛋白在大多数人类乳腺癌中过度表达，但其机制尚未完全明确。微小RNA miR-125b在乳腺癌细胞中表达下调。目前的研究表明，MUC1 3'非翻译区（UTR）含有一个可与miR-125b种子区域结合的位点。结果显示，MUC1 3'UTR可抑制荧光素酶表达，而miR-125b结合位点的突变或缺失可消除这种作用。在BT-549乳腺癌细胞中表达反义miR-125b与MUC1蛋白水平的诱导相关，但与MUC1 mRNA水平无关。反义miR-125b还通过MUC1依赖的机制促进BT-549细胞生长。此外，在ZR-75-1乳腺癌细胞中外源miR-125b的过表达下调了MUC1蛋白水平，而非MUC1转录本水平。已证明用小干扰RNA（siRNA）使ZR-75-1细胞中的MUC1沉默可促进DNA损伤诱导的细胞凋亡。与这些观察结果一致，miR-125b诱导的MUC1水平降低增加了ZR-75-1细胞对顺铂治疗的凋亡反应。这些发现表明，miR-125b抑制MUC1癌蛋白的翻译，因此miR-125b在乳腺癌细胞中发挥肿瘤抑制作用。
