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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 15, 2007 Accepted September 4, 2007 The new tumor suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of pro-angiogenic molecules by myeloma cells and suppresses hypoxia inducible factor (HIF)-1 activity being involved in myeloma-induced angiogenesis Simona Colla, Sara Tagliaferri, Francesca Morandi, Paolo Lunghi, Gaetano Donofrio, Davide Martorana, Cristina Mancini, Mirca Lazzaretti, Laura Mazzera, Lara Ravanetti, Sabrina Bonomini, Luca Ferrari, Claudia Miranda, Marco Ladetto, Tauro Maria Neri, Antonino Neri, Angela Greco, Marcellina Mangoni, Antonio Bonati, Vittorio Rizzoli, and Nicola Giuliani* Hematology and Bone Marrow Transplantation Center, University of Parma, Parma, Italy Department of Clinical Sciences, University of Parma, Parma, Italy "Sezione Malattie Infettive, Dipartimento di Salute Animale", University of Parma, Parma, Italy "Genetica Molecolare e Citogenetica", University of Parma, Parma, Italy Pathology, University of Parma, Parma, Italy "Dipartimento di Genetica, Biologia dei Microrganismi, Antropologia, Evoluzione", University of Parma, Parma, Italy Department of Experimental Oncology, Fondazione IRCCS, "Istituto Nazionale dei Tumori", Milan, Italy Chair of Hematology, University of Torino, Torino, Italy Laboratorio di Genetica Molecolare, Centro di Ricerca Studio Leucemie, University of Milan, Fondazione Policlinico IRCCS, Milan, Italy * Corresponding author; email: nicola.giuliani{at}unipr.it. 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 pro-angiogenic 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 (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 as compared to those with low IL-8 and MVD. Our data indicate that ING4 exerts an inhibitory effect on the production of pro-angiogenic 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: Y. Hu, K. Kirito, K. Yoshida, T. Mitsumori, K. Nakajima, Y. Nozaki, S. Hamanaka, T. Nagashima, M. Kunitama, K. Sakoe, et al. Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan Mol. Cancer Ther., August 1, 2009; 8(8): 2329 - 2338. [Abstract] [Full Text] [PDF] M. S. Fernandes, E. M. Gomes, L. D. Butcher, R. Hernandez-Alcoceba, D. Chang, J. Kansopon, J. Newman, M. J. Stone, and A. W. Tong Growth Inhibition of Human Multiple Myeloma Cells by an Oncolytic Adenovirus Carrying the CD40 Ligand Transgene Clin. Cancer Res., August 1, 2009; 15(15): 4847 - 4856. [Abstract] [Full Text] [PDF] 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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