title: Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis.
abstract: Understanding the mechanism by which tumor cells influence osteoclast differentiation is crucial for improving treatment of osteolytic metastasis. Here, we report broad microRNA (miRNA) expression changes in differentiating osteoclasts after exposure to tumor-conditioned media, in part through activation of NFκB signaling by soluble intracellular adhesion molecule (sICAM1) secreted from bone-metastatic cancer cells. Ectopic expression of multiple miRNAs downregulated during osteoclastogenesis suppresses osteoclast differentiation by targeting important osteoclast genes. Intravenous delivery of these miRNAs in vivo inhibits osteoclast activity and reduces osteolytic bone metastasis. Importantly, serum levels of sICAM1 and two osteoclast miRNAs, miR-16 and miR-378, which are elevated in osteoclast differentiation, correlate with bone metastasis burden. These findings establish miRNAs as potential therapeutic targets and clinical biomarkers of bone metastasis.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Ell
authors.forename: Laura
authors.initials: L
authors.lastname: Mercatali
authors.forename: Toni
authors.initials: T
authors.lastname: Ibrahim
authors.forename: Neil
authors.initials: N
authors.lastname: Campbell
authors.forename: Heidi
authors.initials: H
authors.lastname: Schwarzenbach
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001859:Bone Neoplasms / Q000473:pathology*; D001862:Bone Resorption; D018821:CD18 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000166:cytology*; D010014:Osteolysis
chemical_list: D014408:Biomarkers, Tumor; D018821:CD18 Antigens; D017077:Culture Media, Conditioned; C533895:MIRN141 microRNA, human; C505362:MIRN16 microRNA, human; C578248:MIRN219 microRNA, human; C526012:MIRN378 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1