title: 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 angiogenesis.
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-1alpha (HIF-1alpha) activity and its target gene NIP-3 expression in hypoxic condition. In turn, we show that the inhibition of HIF-1alpha 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.
authors.affiliation: Hematology and Bone Marrow Transplantation Center, University of Parma, Parma, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Colla
authors.forename: Sara
authors.initials: S
authors.lastname: Tagliaferri
authors.forename: Francesca
authors.initials: F
authors.lastname: Morandi
authors.forename: Paolo
authors.initials: P
authors.lastname: Lunghi
authors.forename: Gaetano
authors.initials: G
authors.lastname: Donofrio
authors.forename: Davide
authors.initials: D
authors.lastname: Martorana
authors.forename: Cristina
authors.initials: C
authors.lastname: Mancini
authors.forename: Mirca
authors.initials: M
authors.lastname: Lazzaretti
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzera
authors.forename: Lara
authors.initials: L
authors.lastname: Ravanetti
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bonomini
authors.forename: Luca
authors.initials: L
authors.lastname: Ferrari
authors.forename: Claudia
authors.initials: C
authors.lastname: Miranda
authors.forename: Marco
authors.initials: M
authors.lastname: Ladetto
authors.forename: Tauro Maria
authors.initials: TM
authors.lastname: Neri
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.forename: Angela
authors.initials: A
authors.lastname: Greco
authors.forename: Marcellina
authors.initials: M
authors.lastname: Mangoni
authors.forename: Antonio
authors.initials: A
authors.lastname: Bonati
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rizzoli
authors.forename: Nicola
authors.initials: N
authors.lastname: Giuliani
mesh_terms: D000368:Aged; D042501:Angiogenic Proteins / Q000096:biosynthesis* / Q000235:genetics; D001856:Bone Marrow Examination; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D009101:Multiple Myeloma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000209:etiology*; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D042501:Angiogenic Proteins; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C483230:ING4 protein, human; D016209:Interleukin-8; D025521:Tumor Suppressor Proteins; D053495:Osteopontin