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 α (HIF-1α) activity: Involvement 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 RizzoliNicola Giuliani

Research output: Contribution to journalArticle

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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 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-1α (HIF-1α) activity and its target gene NIP-3 expression in hypoxic condition. In turn, we show that the inhibition of HIF-1α 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.

Original languageEnglish
Pages (from-to)4464-4475
Number of pages12
JournalBlood
Volume110
Issue number13
DOIs
Publication statusPublished - Dec 15 2007

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Hypoxia-Inducible Factor 1
Cell Hypoxia
Growth Inhibitors
Tumor Suppressor Genes
Multiple Myeloma
Interleukin-8
Tumors
Osteopontin
Genes
Molecules
Prolyl Hydroxylases
Small Interfering RNA

ASJC Scopus subject areas

  • Hematology

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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 α (HIF-1α) activity : Involvement in myeloma-induced angiogenesis. / Colla, Simona; Tagliaferri, Sara; Morandi, Francesca; Lunghi, Paolo; Donofrio, Gaetano; Martorana, Davide; Mancini, Cristina; Lazzaretti, Mirca; Mazzera, Laura; Ravanetti, Lara; Bonomini, Sabrina; Ferrari, Luca; Miranda, Claudia; Ladetto, Marco; Neri, Tauro Maria; Neri, Antonino; Greco, Angela; Mangoni, Marcellina; Bonati, Antonio; Rizzoli, Vittorio; Giuliani, Nicola.

In: Blood, Vol. 110, No. 13, 15.12.2007, p. 4464-4475.

Research output: Contribution to journalArticle

Colla, S, Tagliaferri, S, Morandi, F, Lunghi, P, Donofrio, G, Martorana, D, Mancini, C, Lazzaretti, M, Mazzera, L, Ravanetti, L, Bonomini, S, Ferrari, L, Miranda, C, Ladetto, M, Neri, TM, Neri, A, Greco, A, Mangoni, M, Bonati, A, Rizzoli, V & Giuliani, N 2007, '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 α (HIF-1α) activity: Involvement in myeloma-induced angiogenesis', Blood, vol. 110, no. 13, pp. 4464-4475. https://doi.org/10.1182/blood-2007-02-074617
Colla, Simona ; Tagliaferri, Sara ; Morandi, Francesca ; Lunghi, Paolo ; Donofrio, Gaetano ; Martorana, Davide ; Mancini, Cristina ; Lazzaretti, Mirca ; Mazzera, Laura ; Ravanetti, Lara ; Bonomini, Sabrina ; Ferrari, Luca ; Miranda, Claudia ; Ladetto, Marco ; Neri, Tauro Maria ; Neri, Antonino ; Greco, Angela ; Mangoni, Marcellina ; Bonati, Antonio ; Rizzoli, Vittorio ; Giuliani, Nicola. / 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 α (HIF-1α) activity : Involvement in myeloma-induced angiogenesis. In: Blood. 2007 ; Vol. 110, No. 13. pp. 4464-4475.
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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 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-1α (HIF-1α) activity and its target gene NIP-3 expression in hypoxic condition. In turn, we show that the inhibition of HIF-1α 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.",
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T1 - 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 α (HIF-1α) activity

T2 - Involvement in myeloma-induced angiogenesis

AU - Colla, Simona

AU - Tagliaferri, Sara

AU - Morandi, Francesca

AU - Lunghi, Paolo

AU - Donofrio, Gaetano

AU - Martorana, Davide

AU - Mancini, Cristina

AU - Lazzaretti, Mirca

AU - Mazzera, Laura

AU - Ravanetti, Lara

AU - Bonomini, Sabrina

AU - Ferrari, Luca

AU - Miranda, Claudia

AU - Ladetto, Marco

AU - Neri, Tauro Maria

AU - Neri, Antonino

AU - Greco, Angela

AU - Mangoni, Marcellina

AU - Bonati, Antonio

AU - Rizzoli, Vittorio

AU - Giuliani, Nicola

PY - 2007/12/15

Y1 - 2007/12/15

N2 - 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-1α (HIF-1α) activity and its target gene NIP-3 expression in hypoxic condition. In turn, we show that the inhibition of HIF-1α 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.

AB - 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-1α (HIF-1α) activity and its target gene NIP-3 expression in hypoxic condition. In turn, we show that the inhibition of HIF-1α 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.

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