Research Papers:

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

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

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Oncotarget. 2016; 7:25683-25697. https://doi.org/10.18632/oncotarget.8361

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Yun Teng2, Jingyao Mu2, Xin Hu4,5, Abhilash Samykutty2, Xiaoying Zhuang2, Zhongbin Deng2, Lifeng Zhang2, Pengxiao Cao2, Jun Yan2, Donald Miller2, Huang-Ge Zhang1,2,3

1Robley Rex VA Medical Center, Louisville, KY 40206, USA

2James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA

3Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA

4Program in Biostatistics, Bioinformatics and Systems Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA

5Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

Correspondence to:

Huang-Ge Zhang, e-mail: [email protected]

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


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.

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