title: A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance.
abstract: Androgen deprivation therapy is the most effective treatment for advanced prostate cancer, but almost all cancer eventually becomes castration resistant, and the underlying mechanisms are largely unknown. Here, we show that an intrinsic constitutively activated feedforward signaling circuit composed of IκBα/NF-κB(p65), miR-196b-3p, Meis2, and PPP3CC is formed during the emergence of castration-resistant prostate cancer (CRPC). This circuit controls the expression of stem cell transcription factors that drives the high tumorigenicity of CRPC cells. Interrupting the circuit by targeting its individual components significantly impairs the tumorigenicity and CRPC development. Notably, constitutive activation of IκBα/NF-κB(p65) in this circuit is not dependent on the activation of traditional IKKβ/NF-κB pathways that are important in normal immune responses. Therefore, our studies present deep insight into the bona fide mechanisms underlying castration resistance and provide the foundation for the development of CRPC therapeutic strategies that would be highly efficient while avoiding indiscriminate IKK/NF-κB inhibition in normal cells.
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Ji-Hak
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Pathology, Moffitt Cancer Center, 2902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Shohreh Iravani
authors.initials: SI
authors.lastname: Dickinson
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: jlluo@scripps.edu.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Luo
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D018398:Homeodomain Proteins; C491172:MEIS2 protein, human; C542543:MIRN196 microRNA, human; C000602251:MIRN196 microRNA, mouse; D035683:MicroRNAs; C102641:Mrg1 protein, mouse; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C498143:RELA protein, human; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014157:Transcription Factors; C064658:RAG-1 protein; D000072000:NF-KappaB Inhibitor alpha; D019703:Calcineurin; C525675:PPP3CC protein, human; C000602854:PPP3CC protein, mouse
keywords: Meis2; NF-κB; PPP3CC; advanced prostate cancer; androgen deprivation therapy; castration-resistance; castration-resistant prostate cancer; constitutively activated inflammatory signaling; miR-196b-3p; stem cell transcription factors; tumorigenicity