The deregulation of the homeobox genes as homeoboxB (HOXB)-7 has been previously associated to tumor progression and angiogenesis; here we investigated the potential role of HOXB7 in the pro-angiogenic properties of multiple myeloma (MM) cells. We found that HOXB7 was expressed in 10 out of 22 MM patients analyzed at the diagnosis related to high bone marrow angiogenesis and overexpressed in about 40% of myeloma cell lines compared with normal plasma cells. Enforced HOXB7 expression in MM cells by a lentiviral vector significantly modified their transcriptional and angiogenic profile, checked by combined microarray and angiogenesis PCR analyses, upregulating VEGFA, FGF2, MMP2, WNT5a and PDGFA and downregulating thrombospoindin-2. The pro- and anti-angiogenic HOXB7-related gene signature was also validated in a large independent dataset of MM patients. Accordingly, MM-induced vessel formation was significantly increased by HOXB7 overexpression both in vitro angiogenic and chorioallantoic membrane assays, as well as the HOXB7 silencing by small interfering RNA inhibited the production of angiogenic factors, and the pro-angiogenic properties of MM cells. Finally, in SCID-NOD mice we confirmed that HOXB7 overexpression by MM cells stimulated tumor growth, increased MM-associated angiogenesis and the expression of pro-angiogenic genes by microarray analysis supporting the critical role of HOXB7 in the angiogenic switch in MM. Keywords: multiple myeloma; microenvironment; angiogenesis; transcription factors; HOXB7
HOXB7 expression by myeloma cells regulates their pro-angiogenic properties in multiple myeloma patients / Storti, Paola; Donofrio, Gaetano; Colla, S; Airoldi, I; Bolzoni, Marina; Agnelli, L; Abeltino, Manuela; Todoerti, K; Lazzaretti, Mirca; Mancini, C; Ribatti, D; Bonomini, S; Franceschi, Valentina; Pistoia, V; Lisignoli, G; Pedrazzini, A; Cavicchi, O; Neri, A; Rizzoli, Vittorio; Giuliani, Nicola. - In: LEUKEMIA. - ISSN 0887-6924. - 25:(2011), pp. 527-537. [10.1038/leu.2010.270]
HOXB7 expression by myeloma cells regulates their pro-angiogenic properties in multiple myeloma patients
STORTI, Paola;DONOFRIO, Gaetano;BOLZONI, Marina;ABELTINO, Manuela;LAZZARETTI, Mirca;FRANCESCHI, Valentina;RIZZOLI, Vittorio;GIULIANI, Nicola
2011-01-01
Abstract
The deregulation of the homeobox genes as homeoboxB (HOXB)-7 has been previously associated to tumor progression and angiogenesis; here we investigated the potential role of HOXB7 in the pro-angiogenic properties of multiple myeloma (MM) cells. We found that HOXB7 was expressed in 10 out of 22 MM patients analyzed at the diagnosis related to high bone marrow angiogenesis and overexpressed in about 40% of myeloma cell lines compared with normal plasma cells. Enforced HOXB7 expression in MM cells by a lentiviral vector significantly modified their transcriptional and angiogenic profile, checked by combined microarray and angiogenesis PCR analyses, upregulating VEGFA, FGF2, MMP2, WNT5a and PDGFA and downregulating thrombospoindin-2. The pro- and anti-angiogenic HOXB7-related gene signature was also validated in a large independent dataset of MM patients. Accordingly, MM-induced vessel formation was significantly increased by HOXB7 overexpression both in vitro angiogenic and chorioallantoic membrane assays, as well as the HOXB7 silencing by small interfering RNA inhibited the production of angiogenic factors, and the pro-angiogenic properties of MM cells. Finally, in SCID-NOD mice we confirmed that HOXB7 overexpression by MM cells stimulated tumor growth, increased MM-associated angiogenesis and the expression of pro-angiogenic genes by microarray analysis supporting the critical role of HOXB7 in the angiogenic switch in MM. Keywords: multiple myeloma; microenvironment; angiogenesis; transcription factors; HOXB7I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
