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Grapefruit-derived nanovectors deliver miR-18a for treatment of liver metastasis of colon cancer by induction of M1 macrophages

2016; Impact Journals LLC; Volume: 7; Issue: 18 Linguagem: Inglês

10.18632/oncotarget.8361

1949-2553

Yun Teng, Jingyao Mu, Xin Hu, Abhilash Samykutty, Xiaoying Zhuang, Zhongbin Deng, Lifeng Zhang, Pengxiao Cao, Jun Yan, Donald M. Miller, Huang-Ge Zhang,

MicroRNA in disease regulation

// Yun Teng 2 , Jingyao Mu 2 , Xin Hu 4, 5 , Abhilash Samykutty 2 , Xiaoying Zhuang 2 , Zhongbin Deng 2 , Lifeng Zhang 2 , Pengxiao Cao 2 , Jun Yan 2 , Donald Miller 2 , Huang-Ge Zhang 1, 2, 3 1 Robley Rex VA Medical Center, Louisville, KY 40206, USA 2 James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA 3 Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA 4 Program in Biostatistics, Bioinformatics and Systems Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA 5 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Correspondence to: Huang-Ge Zhang, e-mail: H0Zhan17@louisville.edu Keywords: miR-18a, M1 Kupffer cells, grapefruit-derived nanovector, IRF2, liver metastasis of colon cancer Received: November 02, 2015 Accepted: March 10, 2016 Published: March 25, 2016 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.