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

• Published in: The Journal of biological chemistry 2012-12, Vol.287 (50), p.42084-42092
• Main Authors: Hassan, Mohammad Q., Maeda, Yukiko, Taipaleenmaki, Hanna, Zhang, Weibing, Jafferji, Mohammad, Gordon, Jonathan A.R., Li, Zhaoyong, Croce, Carlo M., van Wijnen, Andre J., Stein, Janet L., Stein, Gary S., Lian, Jane B.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Cell Biology; Cell Differentiation; Cell Line, Tumor; Differentiation; Gene Expression Regulation, Neoplastic; Glycoproteins - genetics; Glycoproteins - metabolism; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metastasis; Mice; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - genetics; Neoplasm Metastasis; Osteoblasts; Osteoblasts - metabolism; Osteoblasts - pathology; Osteomimicry; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Wnt Signaling; Wnt Signaling Pathway
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.377515

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. Background: MicroRNAs control cell signaling during osteoblast differentiation. Results: miR-218, which is highly expressed in osteoblasts and cancer cells metastatic to bone, targets three inhibitors of Wnt signaling, Sclerostin, Dickkopf2, and secreted frizzled-related protein2. Conclusion: miR-218 promotes differentiation of normal osteoblast and the osteomimetic bone-homing properties of tumor cells. Significance: miR-218 may be a universal stimulator of Wnt-signaling during bone development and cancer progression.