期刊
CANCER RESEARCH
卷 75, 期 8, 页码 1714-1724出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-2109
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资金
- NIH/National Cancer Institute [CA164688, CA179282, CA118948]
- Department of Defense [PC130594]
- UAB Faculty Development Grant
- Larsen Endowment Fellowship Program
- Mercer University
The tumor-suppressive activity of FOXP3 has been observed in tumor initiation, but the underlying mechanism still remains largely unknown. Here, we identified a FOXP3-microRNA-146 (miR-146)-NF-kappa B axis in vitro and in vivo in prostate cancer cells. We observed that FOXP3 dramatically induced the expression of miR-146a/b, which contributed to transcriptional inhibition of IRAK1 and TRAF6, in prostate cancer cell lines. Tissue-specific deletion of Foxp3 in mouse prostate caused a significant reduction of miR-146a and upregulation of NF-kappa B activation. In addition, prostatic intraepithelial neoplasia lesions were observed in miR-146a-mutant mice as well as in Foxp3-mutant mice. Notably, the NF-kappa B inhibitor bortezomib inhibited cell proliferation and induced apoptosis in prostate epithelial cells, attenuating prostatic intraepithelial neoplasia formation in Foxp3-mutant mice. Our data suggest that the FOXP3-miR-146-NF-kappa B axis has a functional role during tumor initiation in prostate cancer. Targeting the miR-146-NF-kappa B axis may provide a new therapeutic approach for prostate cancers with FOXP3 defects. (C)2015 AACR.
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