A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance
Autor: | Shohreh I. Dickinson, Sun-Jin Park, Jun-Li Luo, Ji-Hak Jeong |
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Rok vydání: | 2017 |
Předmět: |
Male
0301 basic medicine Time Factors Antineoplastic Agents Hormonal Genes myc Mice Transgenic IκB kinase Biology Transfection urologic and male genital diseases Article Androgen deprivation therapy 03 medical and health sciences chemistry.chemical_compound Prostate cancer NF-KappaB Inhibitor alpha Castration Resistance Cell Line Tumor Tumor Cells Cultured medicine Animals Humans Molecular Biology Cell Proliferation Homeodomain Proteins Inflammation Calcineurin Transcription Factor RelA Cancer Androgen Antagonists NF-κB Cell Biology medicine.disease Tumor Burden Gene Expression Regulation Neoplastic MicroRNAs Prostatic Neoplasms Castration-Resistant IκBα Phenotype 030104 developmental biology chemistry Drug Resistance Neoplasm Immunology Neoplastic Stem Cells Cancer research RNA Interference Stem cell Signal Transduction Transcription Factors |
Zdroj: | Molecular Cell. 65:154-167 |
ISSN: | 1097-2765 |
Popis: | Androgen deprivation therapy is the most effective treatment for advanced prostate cancer, however, almost all cancer eventually become castration-resistant, and the underlying mechanisms are largely unknown. Here, we show that an intrinsic constitutively activated feed-forward signaling circuit composed of IκBα/NF-κB(p65), miR-196b-3p, Meis2, 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. |
Databáze: | OpenAIRE |
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