Abstract
The interleukin (IL)-24/melanoma differentiation associated gene-7 (mda-7) is a member of the IL-10 cytokine family. Introduction of the IL-24 gene into a variety of cancer cells suppresses their growth. It has not been shown, however, whether IL-24 can suppress the growth of hepatoma cells. The purpose of this study was to determine whether the mouse (m)IL-24 gene would suppress hepatoma cells in vivo after being delivered via intramuscular electroporation. After mice were given a subcutaneous dorsal injection of ML-1 hepatoma cells, the mIL-24 gene was delivered and suppressed tumor growth. On day 140, 60% of the mIL-24-treated mice (n=10) and 0% (n=10) of the untreated control mice had survived. We also generated a mouse-hepatoma model by injecting ML-1 cells into the spleen, which resulted in tumor metastasis in the liver. Intramuscular electroporation of mIL-24 also inhibited hepatoma-cell growth in the liver. On day 50, 90% of the experimental mice (n=10) and 40% (n=10) of the control mice had survived. Liver tumors in surviving experimental mice were 50% smaller than those in control mice. IL-24 also inhibited tumor vascularization. These results suggest that IL-24 has potential therapeutic value for hepatoma.
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Huang EY, Madireddi MT, Gopalkrishnan RV et al. Genomic structure, chromosomal localization and expression profile of a novel melanoma differentiation associated (mda-7) gene with cancer specific growth suppressing and apoptosis inducing properties. Oncogene 2001; 20: 7051–7063.
Ellerhorst JA, Prieto VG, Ekmekcioglu S et al. Loss of MDA-7 expression with progression of melanoma. J Clin Oncol 2002; 20: 1069–1074.
Ekmekcioglu S, Ellerhorst J, Mhashilkar AM et al. Down-regulated melanoma differentiation associated gene (mda-7) expression in human melanomas. Int J Cancer 2001; 94: 54–59.
Su ZZ, Madireddi MT, Lin JJ et al. The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. Proc Natl Acad Sci USA 1998; 95: 14400–14405.
Saeki T, Mhashilkar A, Chada S, Branch C, Roth JA, Ramesh R . Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro. Gene Therapy 2000; 7: 2051–2057.
Jiang H, Lin JJ, Su ZZ, Goldstein NI, Fisher PB . Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 1995; 11: 2477–2486.
Soo C, Shaw WW, Freymiller E et al. Cutaneous rat wounds express c49a, a novel gene with homology to the human melanoma differentiation associated gene, mda-7. J Cell Biochem 1999; 74: 1–10.
Ramesh R, Mhashilkar AM, Tanaka F et al. Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor. Cancer Res 2003; 63: 5105–5113.
Aihara H, Miyazaki J . Gene transfer into muscle by electroporation in vivo. Nat Biotechnol 1998; 16: 867–870.
Dupuis M, Denis-Mize K, Woo C et al. Distribution of DNA vaccines determines their immunogenicity after intramuscular injection in mice. J Immunol 2000; 165: 2850–2858.
Horton HM, Anderson D, Hernandez P, Barnhart KM, Norman JA, Parker SE . A gene therapy for cancer using intramuscular injection of plasmid DNA encoding interferon alpha. Proc Natl Acad Sci USA 1999; 96: 1553–1558.
Li S, Zhang X, Xia X et al. Intramuscular electroporation delivery of IFN-alpha gene therapy for inhibition of tumor growth located at a distant site. Gene Therapy 2001; 8: 400–407.
Mathiesen I . Electro-permeabilization of skeletal muscle enhances gene transfer in vivo. Gene Therapy 1999; 6: 508–514.
Lee SC, Wu CJ, Wu PY, Huang YL, Wu CW, Tao MH . Inhibition of established subcutaneous and metastatic murine tumors by intramuscular electroporation of the interleukin-12 gene. J Biomed Sci 2003; 10: 73–86.
Schaefer G, Venkataraman C, Schindler U . Cutting edge: FISP (IL-4-induced secreted protein), a novel cytokine-like molecule secreted by Th2 cells. J Immunol 2001; 166: 5859–5863.
Wagner H . The immunobiology of the TLR9 subfamily. Trends Immunol 2004; 25: 381–386.
Krieg AM . Antitumor applications of stimulating toll-like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol Rep 2004; 6: 88–95.
Sauane M, Lebedeva IV, Su ZZ et al. Melanoma differentiation associated gene-7/interleukin-24 promotes tumor cell-specific apoptosis through both secretory and nonsecretory pathways. Cancer Res 2004; 64: 2988–2993.
Sieger KA, Mhashilkar AM, Stewart A et al. The tumor suppressor activity of MDA-7/IL-24 is mediated by intracellular protein expression in NSCLC cells. Mol Ther 2004; 9: 355–367.
Wang M, Tan Z, Thomas EK, Liang P . Conservation of the genomic structure and receptor-mediated signaling between human and rat IL-24. Genes Immun 2004; 5: 363–370.
Chen SH, Hu CP, Chang CM . Hepatitis B virus replication in well differentiated mouse hepatocyte cell lines immortalized by plasmid DNA. Cancer Res 1992; 52: 1329–1335.
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This study was supported by a grant from Chi-Mei Medical Center.
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Chen, WY., Cheng, YT., Lei, HY. et al. IL-24 inhibits the growth of hepatoma cells in vivo. Genes Immun 6, 493–499 (2005). https://doi.org/10.1038/sj.gene.6364233
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DOI: https://doi.org/10.1038/sj.gene.6364233
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