FOXP3-miR-146-NF-κB Axis and Therapy for Precancerous Lesions in Prostate.
FOXP3-miR-146-NF-κB Axis and Therapy for Precancerous Lesions in Prostate.
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DOI：
10.1158/0008-5472.can-14-2109
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发表时间：
2015-04-15
期刊：
影响因子：
11.2
通讯作者：
Wang L
中科院分区：
文献类型：
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作者：
Liu R;Yi B;Wei S;Yang WH;Hart KM;Chauhan P;Zhang W;Mao X;Liu X;Liu CG;Wang L
FOXP3的抑瘤活性已在肿瘤发生过程中被观察到，但其潜在的机制仍不清楚。本研究在体外和体内前列腺癌细胞中鉴定了FOXP3-microRNA-146 (miR-146)-NF-κB轴。我们观察到FOXP3显著诱导miR-146a/b的表达，这有助于抑制IRAK1和TRAF6在前列腺癌细胞系中的转录。小鼠前列腺中Foxp3的组织特异性缺失导致miR-146a的显著降低和NF-κB激活的上调。此外，在miR-146a突变小鼠和Foxp3突变小鼠中观察到前列腺上皮内瘤变病变。值得注意的是，NF-κB抑制剂硼替佐米抑制前列腺上皮细胞增殖，诱导凋亡，减轻Foxp3突变小鼠前列腺上皮内瘤变的形成。我们的数据表明FOXP3-miR-146-NF-κB轴在前列腺癌的肿瘤起始过程中具有功能作用。靶向miR-146-NF-κB轴可能为FOXP3缺陷前列腺癌提供新的治疗途径。
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-κB 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-κB activation. In addition, prostatic intraepithelial neoplasia lesions were observed in miR-146a mutant mice as well as in Foxp3 mutant mice. Notably, the NF-κB 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-κB axis has a functional role during tumor initiation in prostate cancer. Targeting the miR-146-NF-κB axis may provide a new therapeutic approach for prostate cancers with FOXP3 defects.