miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells

Mohammad Q. Hassan, Yukiko Maeda, Hanna Taipaleenmaki, Weibing Zhang, Mohammad Jafferji, Jonathan A R Gordon, Zhaoyong Li, Carlo M. Croce, Andre J van Wijnen, Janet L. Stein, Gary S. Stein, Jane B. Lian

Research output: Contribution to journalArticle

163 Citations (Scopus)

Abstract

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 downregulating 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.

Original languageEnglish (US)
Pages (from-to)42084-42092
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number50
DOIs
StatePublished - Dec 7 2012

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Osteoblasts
Cells
Osteogenesis
Bone
Networks (circuits)
Neoplasms
Wnt Signaling Pathway
Genes
MicroRNAs
Mesenchymal Stromal Cells
Breast
Transcription
Down-Regulation
Epithelial Cells
Breast Neoplasms
Phenotype
Gene Expression
Bone and Bones
Tumors
Growth

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Hassan, M. Q., Maeda, Y., Taipaleenmaki, H., Zhang, W., Jafferji, M., Gordon, J. A. R., ... Lian, J. B. (2012). miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells. Journal of Biological Chemistry, 287(50), 42084-42092. https://doi.org/10.1074/jbc.M112.377515

miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells. / 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.

In: Journal of Biological Chemistry, Vol. 287, No. 50, 07.12.2012, p. 42084-42092.

Research output: Contribution to journalArticle

Hassan, MQ, Maeda, Y, Taipaleenmaki, H, Zhang, W, Jafferji, M, Gordon, JAR, Li, Z, Croce, CM, van Wijnen, AJ, Stein, JL, Stein, GS & Lian, JB 2012, 'miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells', Journal of Biological Chemistry, vol. 287, no. 50, pp. 42084-42092. https://doi.org/10.1074/jbc.M112.377515
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. / miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 50. pp. 42084-42092.
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