title: The role of miR-200a in mammalian epithelial cell transformation.
abstract: Cancer is a multistep disease that begins with malignant cell transformation and frequently culminates in metastasis. MicroRNAs (miRNAs) are small regulatory 21-25 nt RNA molecules and are frequently deregulated in cancer. miR-200a is a member of the miR-200 family, which are known inhibitors of the epithelial-to-mesenchymal transition. As such, the tumor-suppressive role of miR-200a in oncogenesis has been well documented; however, recent studies have found a proliferative role for this miRNA as well as a prometastatic role in the later steps of cancer progression. Little is known about the role of this miRNA in the early stages of cancer, namely, malignant cell transformation. Here, we show that miR-200a alone transforms an immortalized rat epithelial cell line, and miR-200a cooperates with Ras to enhance malignant transformation of an immortalized human epithelial cell line. Furthermore, miR-200a induces cell transformation and tumorigenesis in immunocompromised mice by cooperating with a Ras mutant that activates only the RalGEF effector pathway, but not Ras mutants activating PI3K or Raf effector pathways. This transformative ability is in accordance with miR-200a targeting Fog2 and p53 to activate Akt and directly repress p53 protein levels, respectively. These results demonstrate an oncogenic role for miR-200a and provide a specific cellular context where miR-200a acts as an oncomiR rather than a tumor suppressor by cooperating with an oncogene in malignant cell transformation.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, 319 Abraham Flexner Way, Louisville, KY 40202, USA.
authors.forename: Lindsey E
authors.initials: LE
authors.lastname: Becker
authors.affiliation: St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA and.
authors.forename: Apana Agha L
authors.initials: AA
authors.lastname: Takwi
authors.affiliation: Department of Medical Laboratory and Central Laboratory, The Central Hospital of Wuhan, Wuhan, Hubei 430014, China.
authors.forename: Zhongxin
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, 319 Abraham Flexner Way, Louisville, KY 40202, USA, Department of Medical Laboratory and Central Laboratory, The Central Hospital of Wuhan, Wuhan, Hubei 430014, China yong.li@louisville.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020726:ral Guanine Nucleotide Exchange Factor / Q000378:metabolism
chemical_list: C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D020726:ral Guanine Nucleotide Exchange Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt