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.
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.
Colla
Simona
S
Hematology and Bone Marrow Transplantation Center, University of Parma, Parma, Italy.
Tagliaferri
Sara
S
Morandi
Francesca
F
Lunghi
Paolo
P
Donofrio
Gaetano
G
Martorana
Davide
D
Mancini
Cristina
C
Lazzaretti
Mirca
M
Mazzera
Laura
L
Ravanetti
Lara
L
Bonomini
Sabrina
S
Ferrari
Luca
L
Miranda
Claudia
C
Ladetto
Marco
M
Neri
Tauro Maria
TM
Neri
Antonino
A
Greco
Angela
A
Mangoni
Marcellina
M
Bonati
Antonio
A
Rizzoli
Vittorio
V
Giuliani
Nicola
N
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*
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