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TCF7 is suppressed by the androgen receptor via microRNA-1-mediated downregulation and is involved in the development of resistance to androgen deprivation in prostate cancer.
Siu, M K; Chen, W-Y; Tsai, H-Y; Chen, H-Y; Yin, J J; Chen, C-L; Tsai, Y-C; Liu, Y-N.
Afiliação
  • Siu MK; PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
  • Chen WY; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • Tsai HY; Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • Chen HY; Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • Yin JJ; Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • Chen CL; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • Tsai YC; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • Liu YN; Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
Prostate Cancer Prostatic Dis ; 20(2): 172-178, 2017 06.
Article em En | MEDLINE | ID: mdl-28220803
BACKGROUND: Resistance to androgen deprivation therapy (ADT) represents a key step in the malignant progression of prostate cancer, and mutation to androgen receptor (AR) is one major driver to an androgen-independent phenotype. However, alternative oncogenic pathways that bypass AR signaling have emerged as an important mechanism promoting resistance to ADT. It is known that AR activation can prevent the interaction between ß-catenin and T cell factor/lymphoid enhancer-binding factor (TCF/LEF) family, inhibiting the Wnt signaling pathway. The aim of this study was to determine the role of transcription factor 7 (TCF7), a transcription factor best known as a Wnt effector that forms a complex with ß-catenin, in the development of advanced prostate cancer. We further investigated the molecular mechanisms by which TCF7 is induced when AR signaling is inactivated. METHODS: A novel AR signaling pathway that induces microRNA-1 (miR-1) to suppress metastatic prostate cancer was recently demonstrated (AR-miR-1 signaling axis), and its regulation of Wnt signaling was explored in the current study. Clinical data sets were analyzed for potential targets of AR-miR-1 signaling in the TCF/LEF family, and tissue samples were utilized to validate the relationship. The molecular mechanism and biological functions were demonstrated in prostate cancer cell lines and a mouse xenograft model. RESULTS: We demonstrated a molecular mechanism of AR signaling suppressing TCF7 partly through miR-1-mediated downregulation. TCF7 exhibited oncogenic properties and compromised the tumor-suppressive effects of miR-1. Our results also showed that overexpression of TCF7 or disruption of miR-1 function promoted androgen-independent proliferation. CONCLUSIONS: We demonstrated that the AR-miR-1 axis negatively regulates the novel oncogenic factor, TCF7. Dysregulation of TCF7 promoted a survival advantage and resistance to androgen deprivation, suggesting its therapeutic potential for castration-resistant prostate cancer.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores Androgênicos / MicroRNAs / Fator 1 de Transcrição de Linfócitos T / Neoplasias de Próstata Resistentes à Castração Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores Androgênicos / MicroRNAs / Fator 1 de Transcrição de Linfócitos T / Neoplasias de Próstata Resistentes à Castração Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2017 Tipo de documento: Article