miR-218 Directs a Wnt Signaling Circuit to Promote Differentiation of Osteoblasts and Osteomimicry of Metastatic Cancer Cells
miR-218 Directs a Wnt Signaling Circuit to Promote Differentiation of Osteoblasts and Osteomimicry of Metastatic Cancer Cells
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DOI：
10.1074/jbc.m112.377515
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发表时间：
2012-12-07
影响因子：
4.8
通讯作者：
Lian, Jane B.
中科院分区：
文献类型：
--
作者：
Hassan, Mohammad Q.;Maeda, Yukiko;Lian, Jane B.
微小RNA（miRNAs）负性和转录后调节多个靶基因的表达，以支持骨形成的合成代谢途径。在这里，我们发现miR-218在成骨细胞分化过程中被诱导，并具有强大的成骨特性。miR-218通过激活正Wnt信号环促进骨髓基质细胞的定型和分化在前馈机制中，miR-218通过下调骨生成过程中的三种Wnt信号传导抑制剂来刺激Wnt通路：硬化蛋白（SOST）、Dickkopf 2（DKK 2）和分泌型卷曲相关蛋白2（SFRP 2）。反过来，miR-218表达响应于刺激的Wnt信号传导而上调，并在功能上驱动Wnt相关的转录和成骨细胞分化，从而产生正反馈环。此外，在转移性乳腺癌细胞中，而不是在正常的乳腺上皮细胞中，miR-218增强Wnt活性和成骨细胞基因的异常表达（拟骨），这有助于转移到骨的细胞的归巢和生长。因此，miR-218/Wnt信号通路放大了成骨细胞表型和骨模拟相关的肿瘤活性。
MicroRNAs (miRNAs) negatively and post-transcriptionally regulate expression of multiple target genes to support anabolic pathways for bone formation. Here, we show that miR-218 is induced during osteoblast differentiation and has potent osteogenic properties. miR-218 promotes commitment and differentiation of bone marrow stromal cells by activating a positive Wnt signaling loop. In a feed forward mechanism, miR-218 stimulates the Wnt pathway by down-regulating three Wnt signaling inhibitors during the process of osteogenesis: Sclerostin (SOST), Dickkopf2 (DKK2), and secreted frizzled-related protein2 (SFRP2). In turn, miR-218 expression is up-regulated in response to stimulated Wnt signaling and functionally drives Wnt-related transcription and osteoblast differentiation, thereby creating a positive feedback loop. Furthermore, in metastatic breast cancer cells but not in normal mammary epithelial cells, miR-218 enhances Wnt activity and abnormal expression of osteoblastic genes (osteomimicry) that contribute to homing and growth of cells metastatic to bone. Thus, miR-218/Wnt signaling circuit amplifies both the osteoblast phenotype and osteomimicry-related tumor activity.