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[摘要]：The estrogen-responsive gene Efp promotes the growth of breast cancer cells by stimulating the degradation of a negative cell-cycle regulator, 14-3-3 sigma, and is hence considered a suitable molecular target for breast cancer therapy. The use of small interfering RNA (siRNA) and its derivatives to silence cancer-related genes is being investigated with the aim of identifying clinical applications for these molecules. Recently, it has been shown that DNA-modified siRNA (chimeric siRNA) has good potential in clinical applications, because it induces fewer off-target effects or immune responses in mammalian cells. In the present study, we identified the most specific and effective siRNA (siEfp-1) for silencing Efp expression in MCF-7 breast cancer cells. For this purpose, we used an algorithm that primarily eliminates off-target effects. siEfp-1 considerably suppressed the in vitro proliferation and cell-cycle progression of MCF-7 cells, as well as the in vivo growth of MCF-7 tumors, in athymic mice. DNA-modified siEfp-1 (chimeric siEfp) significantly inhibited the expression of Efp, proliferation of cultured cells and the in vivo growth of MCF-7-derived tumors in athymic mice. In addition, the silencing of Efp expression by siEfp-1 and chimeric siEfp increased the expression of the 14-3-3 sigma protein. These results suggest that siEfp-1 and chimeric siEfp could be useful in breast cancer therapy. Chimeric siEfp, in particular, has a high specificity and induces few side effects and is therefore expected to be used as a novel nucleic acid-based therapeutic agent. Cancer Gene Therapy (2010) 17, 624 632; doi:10.1038/cgt.2010.19; published online 14 May 2010 |
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