FOXP3-microRNA-146-NF-κB as oncotarget.

The X-linked FOXP3 gene is a member of the forkhead box/winged helix family. As a transcription factor, FOXP3 plays an important role in the immune system by acting as a master regulator of transcription for the development and function of regulatory T cells. Additionally, its tumor suppressive activity has been observed during tumor initiation [1]. MicroRNA (miR) plays a role in RNA silencing and in post transcriptional regulation of gene expression. Accumulating data suggest that the miR-146 family, including miR-146a/b, inhibits cancer cell proliferation, invasion and metastasis in human breast and prostate cancers [2-5]. Since miR-146a is overexpressed in Foxp3+ regulatory T cells and is critical for its function in the immune system, there is thought to be a link between miR-146a and the FOXP3 gene [6]. Additionally, nuclear factor-kappaB (NF-κB), a protein complex that controls transcriptional activity of DNA and helps regulate cell survival, was instrumental to the discovery of a novel pathway that may serve as a target of drug therapy for cancer patients. In these two papers, a new axis was identified and is known as the FOXP3-miR-146-NF-κB axis (Fig. 1) [7, 8]. In breast cancer cells, chromatin immunoprecipitation sequencing was used to identify a series of potential FOXP3-targeted miRs [7]. In particular, FOXP3 dramatically induced the expression of miR-146a/b that prevented tumor cell proliferation while also enhancing apoptosis. Functional analyses showed that FOXP3induced miR-146a/b downregulated NF-κB activation by inhibiting the expression of two miR-146 target genes IRAK1 (involved in Toll/IL-1 signaling) and TRAF6 (a member of a family of proteins involved in the regulation of inflammation and apoptosis) [7]. Furthermore, chromatin immunoprecipitation assays revealed that FOXP3 directly bound to the promoter region of miR146a but not to that of miR-146b. In addition, a direct interaction of FOXP3 with NF-κB p65 was identified to regulate a miR-146a-NF-κB negative feedback regulation loop in normal breast epithelial cells as well as in breast cancer cells (Figure 1). In vivo analyses also validated that FOXP3-mediated induction of miR-146a resulted in the downregulation of IRAK1 and TRAF6 and subsequently inhibited NF-κB activation, thus leading to tumor suppression in breast cancer cells. Conversely, FOXP3mediated inhibition of cell proliferation and tumor growth and its induction of apoptosis were partially blocked by miR-146a/b inhibitors, indicating a contribution of miR146a/b to FOXP3-triggered tumor suppression. It has been determined that the FOXP3-miR-146NF-κB axis serves as a target pathway for diminishing the pre-prostate cancerous state in the animal model [8]. In prostate cancer cells, it was also validated that FOXP3 transcriptionally inhibits IRAK1 and TRAF6 through an induced expression of miR-146a/b [8]. Hybridization analysis indicated that a low expression of miR-146a/b was observed in prostate cancer cell lines, while a high expression of miR-146a/b was seen in normal prostate tissues [4]. Transfection of miR-146a into prostate cancer cells resulted in a marked reduction of cell invasion, proliferation and metastasis to bone marrow [4, 5], suggesting that miR-146a functions as a tumor suppressor in prostate cancer cells. The functional FOXP3-miR-146NF-κB axis during tumor initiation in prostate cancer cells Editorial