miR-218 Directs a Wnt Signaling Circuit to Promote Differentiation of Osteoblasts and Osteomimicry of Metastatic Cancer Cells

被引:252
作者
Hassan, Mohammad Q. [1 ,2 ]
Maeda, Yukiko [1 ,2 ]
Taipaleenmaki, Hanna [1 ,2 ]
Zhang, Weibing [1 ,2 ]
Jafferji, Mohammad [1 ,2 ]
Gordon, Jonathan A. R. [1 ,2 ]
Li, Zhaoyong [1 ,2 ]
Croce, Carlo M. [3 ,4 ]
van Wijnen, Andre J. [1 ,2 ]
Stein, Janet L. [1 ,2 ]
Stein, Gary S. [1 ,2 ]
Lian, Jane B. [1 ,2 ]
机构
[1] Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA 01655 USA
[2] Univ Massachusetts, Sch Med, Ctr Canc, Worcester, MA 01655 USA
[3] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA
[4] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA
基金
美国国家卫生研究院;
关键词
BONE SIALOPROTEIN; WNT/BETA-CATENIN; BREAST; PROGRESSION; SCLEROSTIN; RUNX2; GENE; OSTEOPONTIN; INHIBITORS; MICRORNAS;
D O I
10.1074/jbc.M112.377515
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:42084 / 42092
页数:9
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