miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells.
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.
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Mohammad Q
MQ
Hassan
Yukiko
Y
Maeda
Hanna
H
Taipaleenmaki
Weibing
W
Zhang
Mohammad
M
Jafferji
Jonathan A R
JA
Gordon
Zhaoyong
Z
Li
Carlo M
CM
Croce
Andre J
AJ
van Wijnen
Janet L
JL
Stein
Gary S
GS
Stein
Jane B
JB
Lian
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009362:Neoplasm Metastasis; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D060449:Wnt Signaling Pathway; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D035683:MicroRNAs; D012334:RNA, Neoplasm; C405060:Dkk2 protein, mouse; C547684:MIRN218 microRNA, mouse; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C486030:Sost protein, mouse