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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4464-4475. Prepublished online as a Blood First Edition Paper on September 11, 2007; DOI 10.1182/blood-2007-02-074617. This Article Full Text Full Text (PDF) Erratum (v112,p2170) All Versions of this Article: blood-2007-02-074617v1 110/13/4464    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Colla, S. Articles by Giuliani, N. Search for Related Content PubMed PubMed Citation Articles by Colla, S. Articles by Giuliani, N. Related Collections Hemostasis, Thrombosis, and Vascular Biology Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 (HIF-1) activity: involvement in myeloma-induced angiogenesis Simona Colla1, Sara Tagliaferri1, Francesca Morandi1, Paolo Lunghi2, Gaetano Donofrio3, Davide Martorana4, Cristina Mancini5, Mirca Lazzaretti6, Laura Mazzera2, Lara Ravanetti3, Sabrina Bonomini1, Luca Ferrari1, Claudia Miranda7, Marco Ladetto8, Tauro Maria Neri4, Antonino Neri9, Angela Greco7, Marcellina Mangoni1, Antonio Bonati1,2, Vittorio Rizzoli1, and Nicola Giuliani1 1 Hematology and Bone Marrow Transplantation Center, University of Parma, Parma; 2 Department of Clinical Sciences, University of Parma, Parma; 3 Sezione Malattie Infettive, Dipartimento di Salute Animale, University of Parma, Parma; 4 Genetica Molecolare e Citogenetica, University of Parma, Parma; 5 Pathology, University of Parma, Parma; 6 Dipartimento di Genetica, Biologia dei Microrganismi, Antropologia, Evoluzione, University of Parma, Parma; 7 Department of Experimental Oncology, Fondazione Istituti di ricovero e cura a carattere scientifico (IRCCS), Istituto Nazionale dei Tumori, Milan; 8 Hematology, University of Torino, Torino; and 9 Laboratorio di Genetica Molecolare, Centro di Ricerca Studio Leucemie, University of Milan, Fondazione Policlinico IRCCS, Milan, Italy Angiogenesis has a critical role in the pathophysiology of multiple myeloma (MM); however, the molecular mechanisms underlying this process are not completely elucidated. The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) has been recently implicated in solid tumors as a repressor of angiogenesis. In this study, we found that ING4 expression in MM cells was correlated with the expression of the proangiogenic molecules interleukin-8 (IL-8) and osteopontin (OPN). Moreover, we demonstrate that ING4 suppression in MM cells up-regulated IL-8 and OPN, increasing the hypoxia inducible factor-1 (HIF-1) activity and its target gene NIP-3 expression in hypoxic condition. In turn, we show that the inhibition of HIF-1 by siRNA suppressed IL-8 and OPN production by MM cells under hypoxia. A direct interaction between ING4 and the HIF prolyl hydroxylase 2 (HPH-2) was also demonstrated. Finally, we show that ING4 suppression in MM cells significantly increased vessel formation in vitro, blunted by blocking IL-8 or OPN. These in vitro observations were confirmed in vivo by finding that MM patients with high IL-8 production and microvascular density (MVD) have significantly lower ING4 levels compared with those with low IL-8 and MVD. Our data indicate that ING4 exerts an inhibitory effect on the production of proangiogenic molecules and consequently on MM-induced angiogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Zhang, M. Sattler, G. Tonon, C. Grabher, S. Lababidi, A. Zimmerhackl, M. S. Raab, S. Vallet, Y. Zhou, M.-A. Cartron, et al. Targeting Angiogenesis via a c-Myc/Hypoxia-Inducible Factor-1{alpha}-Dependent Pathway in Multiple Myeloma Cancer Res., June 15, 2009; 69(12): 5082 - 5090. [Abstract] [Full Text] [PDF] F. Fang, L.-B. Luo, Y.-M. Tao, F. Wu, and L.-Y. Yang Decreased Expression of Inhibitor of Growth 4 Correlated with Poor Prognosis of Hepatocellular Carcinoma Cancer Epidemiol. Biomarkers Prev., February 1, 2009; 18(2): 409 - 416. [Abstract] [Full Text] [PDF]

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