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Roles for MicroRNAs, miR-93 and miR-130b, and Tumor Protein 53–Induced Nuclear Protein 1 Tumor Suppressor in Cell Growth Dysregulation by Human T-Cell Lymphotrophic Virus 1

¹ Molecular Virology Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland; ² Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan; ³ Institut National de la Santé et de la Recherche Médicale, U624, Stress Cellulaire, IFR 137-Institut de Cancerologie et Immunologie de Marseille, Universite de la Mediterranee, Marseille, France; ⁴ Laboratoire de Virologie Moleculaire, Institut de Genetique Humaine, Centre National de la Recherche Scientifique, UPR1142, Montpellier, France; and ⁵ Department of Microbiology and Immunology, University of Arizona Health Sciences Center, Tucson, Arizona

Requests for reprints: Kuan-Teh Jeang, Building 4, Room 306, 9000 Rockville Pike, Bethesda, MD 20892-0460. Phone: 301-496-6680; Fax: 301-480-3686; E-mail: kj7e{at}nih.gov.

Key Words: HTLV-1 • Adult T-cell leukemia • miRNA • transformation • TP53INP1

A role for microRNAs (miRNA) in human T-cell leukemia virus 1 (HTLV-1)–mediated cellular transformation has not been described. Here, we profiled miRNA expression in HTLV-1–transformed human T-cell lines and primary peripheral blood mononuclear cells from adult T-cell leukemia patients. Analyses of 11 different profiles revealed six miRNAs that were consistently up-regulated. Two of the up-regulated miRNAs (miR-93 and miR-130b) target the 3' untranslated region (3'UTR) of the mRNA for a tumor suppressor protein, tumor protein 53–induced nuclear protein 1 (TP53INP1). A low expression level of TP53INP1 protein was found in HTLV-1–transformed cells. Additionally, when antagomirs were used to knock down miR-93 and miR-130b in these cells, the expression of TP53INP1 was increased, suggesting that the latter is regulated inside cells by the former. A role for TP53INP1 in regulating cell growth was established by experiments that showed that enhanced TP53INP1 expression increased apoptosis. Collectively, the findings implicate a miR-93/miR-130b-TP53INP1 axis that affects the proliferation and survival of HTLV-1–infected/transformed cells. [Cancer Res 2008;68(21):8976–85]

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