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.
|Titolo:||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 alpha (HIF-1alpha) activity : involvement in myeloma-induced angiogenes|
|Parole Chiave:||BONE-MARROW ANGIOGENESIS ; HUMAN MULTIPLE-MYELOMA ; KAPPA-B ACTIVATION ; UNDETERMINED SIGNIFICANCE ; MONOCLONAL GAMMOPATHY ; PROLYL HYDROXYLASES ; DISEASE PROGRESSION ; SPLICE VARIANTS ; MESSENGER-RNA ; PROTEIN ING4|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Data di pubblicazione:||15-dic-2007|
|Digital Object Identifier (DOI):||10.1182/blood-2007-02-074617|
|Appare nelle tipologie:||01 - Articolo su periodico|