A regulatory microRNA network controls endothelial cell phenotypic switch during sprouting angiogenesis
Stefania Rosano,
Davide Corà,
Sushant Parab,
Serena Zaffuto,
Claudio Isella,
Roberta Porporato,
Roxana Maria Hoza,
Raffaele A Calogero,
Chiara Riganti,
Federico Bussolino,
Alessio Noghero
Affiliations
Stefania Rosano
Department of Oncology, University of Turin, Candiolo, Italy; Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy
Davide Corà
Department of Translational Medicine, Piemonte Orientale University, Novara, Italy; Center for Translational Research on Autoimmune and Allergic Diseases - CAAD, Novara, Italy
Sushant Parab
Department of Oncology, University of Turin, Candiolo, Italy; Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy
Serena Zaffuto
Department of Oncology, University of Turin, Candiolo, Italy; Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy
Claudio Isella
Department of Oncology, University of Turin, Candiolo, Italy; Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy
Roberta Porporato
Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy
Roxana Maria Hoza
Department of Oncology, University of Turin, Candiolo, Italy; Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy
Raffaele A Calogero
Molecular Biotechnology Center, Department of Biotechnology and Health Sciences, University of Turin, Turin, Italy
Chiara Riganti
Department of Oncology, University of Turin, Candiolo, Italy
Federico Bussolino
Department of Oncology, University of Turin, Candiolo, Italy; Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy
Angiogenesis requires the temporal coordination of the proliferation and the migration of endothelial cells. Here, we investigated the regulatory role of microRNAs (miRNAs) in harmonizing angiogenesis processes in a three-dimensional in vitro model. We described a microRNA network which contributes to the observed down- and upregulation of proliferative and migratory genes, respectively. Global analysis of miRNA–target gene interactions identified two sub-network modules, the first organized in upregulated miRNAs connected with downregulated target genes and the second with opposite features. miR-424–5p and miR-29a-3p were selected for the network validation. Gain- and loss-of-function approaches targeting these microRNAs impaired angiogenesis, suggesting that these modules are instrumental to the temporal coordination of endothelial migration and proliferation. Interestingly, miR-29a-3p and its targets belong to a selective biomarker that is able to identify colorectal cancer patients who are responding to anti-angiogenic treatments. Our results provide a view of higher-order interactions in angiogenesis that has potential to provide diagnostic and therapeutic insights.
