title: FOXP3-miR-146-NF-κB Axis and Therapy for Precancerous Lesions in Prostate.
abstract: 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.
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 Pediatric Surgery, Tongji Hospital of Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yi
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Shi
authors.initials: S
authors.lastname: Wei
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 Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Hart
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Chauhan
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama. Institute for the Endemic Fluorosis Control, Chinese Center for Endemic Disease Control, Harbin Medical University, Harbin, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Xicheng
authors.initials: X
authors.lastname: Mao
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. 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; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011719:Pyrazines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D001897:Boronic Acids; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D011719:Pyrazines; D000069286:Bortezomib