title: 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.
abstract: 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 β-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 β-catenin, in the development of advanced prostate cancer. We further investigated the molecular mechanisms by which TCF7 is induced when AR signaling is inactivated.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.|Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: M K
authors.initials: MK
authors.lastname: Siu
authors.affiliation: Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: W-Y
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Tsai
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Yin
authors.affiliation: Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: C-L
authors.initials: CL
authors.lastname: Chen
authors.affiliation: PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.|Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Tsai
authors.affiliation: PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.|Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Y-N
authors.initials: YN
authors.lastname: Liu
mesh_terms: D000728:Androgens / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D051822:T Cell Transcription Factor 1 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000728:Androgens; C544547:MIRN1 microRNA, human; D035683:MicroRNAs; D011944:Receptors, Androgen; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human