title: MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes.
abstract: Metastasis causes most cancer deaths, but is incompletely understood. MicroRNAs can regulate metastasis, but it is not known whether a single miRNA can regulate metastasis in primary cancer models in vivo. We compared the expression of miRNAs in metastatic and nonmetastatic primary mouse sarcomas and found that microRNA-182 (miR-182) was markedly overexpressed in some tumors that metastasized to the lungs. By utilizing genetically engineered mice with either deletion of or overexpression of miR-182 in primary sarcomas, we discovered that deletion of miR-182 substantially decreased, while overexpression of miR-182 considerably increased, the rate of lung metastasis after amputation of the tumor-bearing limb. Additionally, deletion of miR-182 decreased circulating tumor cells (CTCs), while overexpression of miR-182 increased CTCs, suggesting that miR-182 regulates intravasation of cancer cells into the circulation. We identified 4 miR-182 targets that inhibit either the migration of tumor cells or the degradation of the extracellular matrix. Notably, restoration of any of these targets in isolation did not alter the metastatic potential of sarcoma cells injected orthotopically, but the simultaneous restoration of all 4 targets together substantially decreased the number of metastases. These results demonstrate that a single miRNA can regulate metastasis of primary tumors in vivo by coordinated regulation of multiple genes.
authors.forename: Mohit
authors.initials: M
authors.lastname: Sachdeva
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Mito
authors.forename: Chang-Lung
authors.initials: CL
authors.lastname: Lee
authors.forename: Minsi
authors.initials: M
authors.lastname: Zhang
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Li
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Dodd
authors.forename: David
authors.initials: D
authors.lastname: Cason
authors.forename: Lixia
authors.initials: L
authors.lastname: Luo
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.forename: David
authors.initials: D
authors.lastname: Van Mater
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gladdy
authors.forename: Dina C
authors.initials: DC
authors.lastname: Lev
authors.forename: Diana M
authors.initials: DM
authors.lastname: Cardona
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
mesh_terms: D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism; D017353:Gene Deletion; D005818:Genetic Engineering; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism*; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C538984:Mirn182 microRNA, human; C540524:Mirn182 microRNA, mouse