title: Grapefruit-derived nanovectors deliver miR-18a for treatment of liver metastasis of colon cancer by induction of M1 macrophages.
abstract: Liver metastasis accounts for many of the cancer deaths in patients. Effective treatment for metastatic liver tumors is not available. Here, we provide evidence for the role of miR-18a in the induction of liver M1 (F4/80+interferon gamma (IFNγ)+IL-12+) macrophages. We found that miR-18a encapsulated in grapefruit-derived nanovector (GNV) mediated inhibition of liver metastasis that is dependent upon the induction of M1 (F4/80+IFNγ+IL-12+) macrophages; depletion of macrophages eliminated its anti-metastasis effect. Furthermore, the miR-18a mediated induction of macrophage IFNγ by targeting IRF2 is required for subsequent induction of IL-12. IL-12 then activates natural killer (NK) and natural killer T (NKT) cells for inhibition of liver metastasis of colon cancer. This conclusion is supported by the fact that knockout of IFNγ eliminates miR-18a mediated induction of IL-12, miR-18a treatment has an anti-metastatic effects in T cell deficient mice but there is no anti-metastatic effect on NK and NKT deficient mice. Co-delivery of miR-18a and siRNA IL-12 to macrophages did not result in activation of co-cultured NK and NKT cells. Taken together our results indicate that miR-18a can act as an inhibitor for liver metastasis through induction of M1 macrophages.
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Teng
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Jingyao
authors.initials: J
authors.lastname: Mu
authors.affiliation: Program in Biostatistics, Bioinformatics and Systems Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.|Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Abhilash
authors.initials: A
authors.lastname: Samykutty
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Zhongbin
authors.initials: Z
authors.lastname: Deng
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Pengxiao
authors.initials: P
authors.lastname: Cao
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Miller
authors.affiliation: Robley Rex VA Medical Center, Louisville, KY 40206, USA.|James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.|Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Huang-Ge
authors.initials: HG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D032083:Citrus paradisi; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008055:Lipids; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000556:secondary*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D035683:MicroRNAs / Q000276:immunology / Q000494:pharmacology*; D053758:Nanoparticles; D010936:Plant Extracts
chemical_list: D008055:Lipids; D035683:MicroRNAs; D010936:Plant Extracts
keywords: IRF2; M1 Kupffer cells; grapefruit-derived nanovector; liver metastasis of colon cancer; miR-18a