title: Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis.
abstract: Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR-miR-1-SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes.
authors: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan liuy@tmu.edu.tw kellyka@mail.nih.gov.
authors: Yen-Nien
authors: YN
authors: Liu
authors: Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: JuanJuan
authors: http://orcid.org/0000-0001-6739-5463
authors: J
authors: Yin
authors: Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Ben
authors: B
authors: Barrett
authors: Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Heather
authors: H
authors: Sheppard-Tillman
authors: Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Jiangsu, China.
authors: Dongmei
authors: D
authors: Li
authors: Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Orla M
authors: OM
authors: Casey
authors: Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Lei
authors: L
authors: Fang
authors: Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Paul G
authors: PG
authors: Hynes
authors: Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Amir H
authors: AH
authors: Ameri
authors: Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA liuy@tmu.edu.tw kellyka@mail.nih.gov.
authors: Kathleen
authors: K
authors: Kelly
mesh_terms: D000728:Androgens / Q000235:genetics*; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D019061:src-Family Kinases / Q000235:genetics*
chemical_list: D000728:Androgens; C544547:MIRN1 microRNA, human; D035683:MicroRNAs; D011944:Receptors, Androgen; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases