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 tumorsuppressor 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.

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{alpha} activity being involved in myeloma-induced angiogenesis / Colla, S; Tagliaferri, Sara; Morandi, F; Lunghi, Paolo; Donofrio, Gaetano; Martorana, D; Mancini, C; Lazzaretti, Mirca; Mazzera, L; Ravanetti, L; Bonomini, S; Ferrari, L; Miranda, C; Ladetto, M; Neri, Tauro Maria; Neri, A; Greco, A; Mangoni, Marcellina; Bonati, Antonio; Rizzoli, Vittorio; Giuliani, Nicola. - In: BLOOD. - ISSN 0006-4971. - 110(13):(2007), pp. 4464-4475. [10.1182/blood-2007-02-074617]

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{alpha} activity being involved in myeloma-induced angiogenesis.

TAGLIAFERRI, Sara;LUNGHI, Paolo;DONOFRIO, Gaetano;LAZZARETTI, Mirca;NERI, Tauro Maria;MANGONI, Marcellina;BONATI, Antonio;RIZZOLI, Vittorio;GIULIANI, Nicola
2007

Abstract

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 tumorsuppressor 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.
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{alpha} activity being involved in myeloma-induced angiogenesis / Colla, S; Tagliaferri, Sara; Morandi, F; Lunghi, Paolo; Donofrio, Gaetano; Martorana, D; Mancini, C; Lazzaretti, Mirca; Mazzera, L; Ravanetti, L; Bonomini, S; Ferrari, L; Miranda, C; Ladetto, M; Neri, Tauro Maria; Neri, A; Greco, A; Mangoni, Marcellina; Bonati, Antonio; Rizzoli, Vittorio; Giuliani, Nicola. - In: BLOOD. - ISSN 0006-4971. - 110(13):(2007), pp. 4464-4475. [10.1182/blood-2007-02-074617]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2294398
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