title: Epidermal growth factor receptor signaling promotes metastatic prostate cancer through microRNA-96-mediated downregulation of the tumor suppressor ETV6.
abstract: It has been suggested that ETV6 serves as a tumor suppressor; however, its molecular regulation and cellular functions remain unclear. We used prostate cancer as a model system and demonstrated a molecular mechanism in which ETV6 can be regulated by epidermal growth factor receptor (EGFR) signaling through microRNA-96 (miR-96)-mediated downregulation. In addition, EGFR acts as a transcriptional coactivator that binds to the promoter of primary miR-96 and transcriptionally regulates miR-96 levels. We analyzed two sets of clinical prostate cancer samples, confirmed association patterns that were consistent with the EGFR-miR-96-ETV6 signaling model and demonstrated that the reduced ETV6 levels were associated with malignant prostate cancer. Based on results derived from multiple approaches, we identified the biological functions of ETV6 as a tumor suppressor that inhibits proliferation and metastasis in prostate cancer. We present a molecular mechanism in which EGFR activation leads to the induction of miR-96 expression and suppression of ETV6, which contributes to prostate cancer progression.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yuan-Chin
authors.initials: YC
authors.lastname: Tsai
authors.affiliation: Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Yu
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; Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Man Kit
authors.initials: MK
authors.lastname: Siu
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hong-Yuan
authors.initials: HY
authors.lastname: Tsai
authors.affiliation: Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Juan Juan
authors.initials: JJ
authors.lastname: Yin
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. Electronic address: liuy@tmu.edu.tw.
authors.forename: Yen-Nien
authors.initials: YN
authors.lastname: Liu
mesh_terms: D000818:Animals; D001665:Binding Sites; D001859:Bone Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D066246:ErbB Receptors; D035683:MicroRNAs; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C541492:MIRN96 microRNA, human; C512478:EGFR protein, human
keywords: Bone metastasis; ETV6; Epidermal growth factor receptor (EGFR); Prostate cancer; microRNA (miR)-96