title: Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization.
abstract: Although the role of miR-200s in regulating E-cadherin expression and epithelial-to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin-dependent epithelial traits and Sec23a-mediated tumor cell secretome.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
authors.forename: Manav
authors.initials: M
authors.lastname: Korpal
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Ell
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.forename: Toni
authors.initials: T
authors.lastname: Ibrahim
authors.forename: Mario A
authors.initials: MA
authors.lastname: Blanco
authors.forename: Toni
authors.initials: T
authors.lastname: Celià-Terrassa
authors.forename: Laura
authors.initials: L
authors.lastname: Mercatali
authors.forename: Zia
authors.initials: Z
authors.lastname: Khan
authors.forename: Hani
authors.initials: H
authors.lastname: Goodarzi
authors.forename: Yuling
authors.initials: Y
authors.lastname: Hua
authors.forename: Yong
authors.initials: Y
authors.lastname: Wei
authors.forename: Guohong
authors.initials: G
authors.lastname: Hu
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism*; D046228:Microarray Analysis; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D018709:Statistics, Nonparametric; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D015820:Cadherins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C079038:Sec23a protein, mouse; D033921:Vesicular Transport Proteins