title: miR-30 as a tumor suppressor connects EGF/Src signal to ERG and EMT.
abstract: Src tyrosine kinase (Src) is implicated in the development of bone metastasis and castration resistance of prostate cancer. Src inhibitors are currently being tested in clinical trials for such diseases. Understanding the molecular and cellular actions of Src inhibitors holds the key to future improvement of this line of therapy. Here we describe the microRNA expression profiles modulated by two Src inhibitors and demonstrate that the miR-30 family members are the most prominently induced species. Consistent with its tumor suppressor role, miR-30 is downmodulated by oncogenic signals such as epidermal growth factor (EGF) and hepatocyte growth factor, and is generally underexpressed in prostate cancer specimens. A number of epithelial-to-mesenchymal transition (EMT)-associated genes are predicted targets of miR-30. Among these genes the Ets-related gene (ERG) is the most frequently overexpressed oncogene in prostate cancer activated by genomic fusion events between promoter upstream sequences of the TMPRSS2 and coding sequences of ERG. We showed by ERG 3' untranslated region reporter and mutagenesis assays that ERG is a direct target of miR-30. Overexpression of miR-30 in prostate cancer cells suppresses EMT phenotypes and inhibits cell migration and invasion. It also inhibits the in vitro and in vivo growth of VCaP cells, which depends on TMPRSS2-ERG for proliferation. TMPRSS2-ERG is generally regulated by androgen at the transcriptional level. Our finding reveals a new post-transcriptional mechanism of TMPRSS2-ERG regulation by Src and growth signals via miR-30 providing a rationale for targeting ERG-positive castration-resistant tumors with Src inhibitors.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California-Davis, Davis, CA, USA.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Kao
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California-Davis, Davis, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Martiniez
authors.affiliation: Department of Urology, University of California-Davis, Sacramento, CA, USA.
authors.forename: X-B
authors.initials: XB
authors.lastname: Shi
authors.affiliation: Department of Urology, University of California-Davis, Sacramento, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Urology, University of California-Davis, Sacramento, CA, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Evans
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dobi
authors.affiliation: Department of Urology, University of California-Davis, Sacramento, CA, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: deVere White
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, University of California-Davis, Davis, CA, USA [2] Institute of Molecular and Genomic Medicine, National Health Research Institutes, Maioli, Taiwan [3] Translational Medicine and Integrated Lab, Taipei Medical University, Taipei, Taiwan.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Kung
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D016147:Genes, Tumor Suppressor; D064593:Heterografts; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000071230:Transcriptional Regulator ERG; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C072312:ERG protein, human; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; C515553:TMPRSS2-ERG fusion protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D004815:Epidermal Growth Factor; D019061:src-Family Kinases