2026-04-27T01:59:26Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/106932024-11-29T13:51:28Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Leinhäuser, Ines author Richter, Andrea author Lee, Misu author Höfig, Ines author Anastasov, Nataša author Fend, Falko author Ercolino, Tonino author Mannelli, Massimo author Gimenez-Roqueplo, Anne-Paule author Robledo, Mercedes author de Krijger, Ronald author Beuschlein, Felix author Atkinson, Michael J author Pellegata, Natalia S author 2015-11-17 BMP7 is a growth factor playing pro- or anti-oncogenic roles in cancer in a cell type-dependent manner. We previously reported that the BMP7 gene is overexpressed in pheochromocytomas (PCCs) developing in MENX-affected rats and human patients. Here, analyzing a large cohort of PCC patients, we found that 72% of cases showed elevated levels of the BMP7 protein. To elucidate the role of BMP7 in PCC, we modulated its levels in PCC cell lines (overexpression in PC12, knockdown in MPC and MTT cells) and conducted functional assays. Active BMP signaling promoted cell proliferation, migration, and invasion, and sustained survival of MENX rat primary PCC cells. In PCC, BMP7 signals through the PI3K/AKT/mTOR pathway and causes integrin β1 up-regulation. Silencing integrin β1 in PC12 cells suppressed BMP7-mediated oncogenic features. Treatment of MTT cells with DMH1, a novel BMP antagonist, suppressed proliferation and migration. To verify the clinical applicability of our findings, we evaluated a dual PI3K/mTOR inhibitor (NVP-BEZ235) in MENX-affected rats in vivo. PCCs treated with NVP-BEZ235 had decreased proliferation and integrin β1 levels, and higher apoptosis. Altogether, BMP7 activates pro-oncogenic pathways in PCC. Downstream effectors of BMP7-mediated signaling may represent novel targets for treating progressive/inoperable PCC, still orphan of effective therapy. Oncotarget . 2015;6(36):39111-26. http://hdl.handle.net/20.500.12105/10693 26337467 10.18632/oncotarget.4912 1949-2553 Oncotarget ENDOCRINE NEOPLASIA SYNDROME BREAST-CANCER CELLS TGF-BETA MALIGNANT PHEOCHROMOCYTOMA CLINICAL-SIGNIFICANCE SIGNALING PATHWAYS PI3K/AKT PATHWAY GROWTH-FACTOR EXPRESSION MIGRATION Oncogenic features of the bone morphogenic protein 7 (BMP7) in pheochromocytoma.