title: FOXP3 Controls an miR-146/NF-κB Negative Feedback Loop That Inhibits Apoptosis in Breast Cancer Cells.
abstract: FOXP3 functions not only as the master regulator in regulatory T cells, but also as an X-linked tumor suppressor. The tumor-suppressive activity of FOXP3 has been observed in tumor initiation, but its role during tumor progression remains controversial. Moreover, the mechanism of FOXP3-mediated tumor-suppressive activity remains largely unknown. Using chromatin immunoprecipitation (ChIP) sequencing, we identified a series of potential FOXP3-targeted miRNAs in MCF7 cells. Notably, FOXP3 significantly induced the expression of miR-146a/b. In vitro, FOXP3-induced miR-146a/b prevented tumor cell proliferation and enhanced apoptosis. Functional analyses in vitro and in vivo revealed that FOXP3-induced miR-146a/b negatively regulates NF-κB activation by inhibiting the expression of IRAK1 and TRAF6. In ChIP assays, FOXP3 directly bound the promoter region of miR-146a but not of miR-146b, and FOXP3 interacted directly with NF-κB p65 to regulate an miR-146-NF-κB negative feedback regulation loop in normal breast epithelial and tumor cells, as demonstrated with luciferase reporter assays. Although FOXP3 significantly inhibited breast tumor growth and migration in vitro and metastasis in vivo, FOXP3-induced miR-146a/b contributed only to the inhibition of breast tumor growth. These data suggest that miR-146a/b contributes to FOXP3-mediated tumor suppression during tumor growth by triggering apoptosis. The identification of a FOXP3-miR-146-NF-κB axis provides an underlying mechanism for disruption of miR-146 family member expression and constitutive NF-κB activation in breast cancer cells. Linking the tumor suppressor function of FOXP3 to NF-κB activation reveals a potential therapeutic approach for cancers with FOXP3 defects.
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama. lwang12@uab.edu runhua@uab.edu.
authors.forename: Runhua
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama. Department of Endocrinology, ShengJing Hospital of China Medical University, Shenyang, PR China.
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Dongquan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia.
authors.forename: Wei-Hsiung
authors.initials: WH
authors.lastname: Yang
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Dugas
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, District of Columbia.
authors.forename: Fei
authors.initials: F
authors.lastname: Tang
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, District of Columbia.
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, District of Columbia.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama. lwang12@uab.edu runhua@uab.edu.
authors.forename: Lizhong
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D025461:Feedback, Physiological; D005260:Female; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B