Prognostic value of the Hippo pathway transcriptional coactivators YAP/TAZ and β1-integrin in conventional osteosarcoma

// Corinne Bouvier 1,2 , Nicolas Macagno 1,2 , Quy Nguyen 1 , Anderson Loundou 3,4 , Carine Jiguet-Jiglaire 1 , Jean-Claude Gentet 5 , Jean-Luc Jouve 6 , Alexandre Rochwerger 7 , Jean-Camille Mattei 1,7 , Daniel Bouvard 8 and Sébastien Salas 1,2 1 Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France 2 Department of Pathology, APHM, Timone Hospital, Marseille, France 3 Department of Public Health, Aix-Marseille University (AMU), Faculty of Medecine, EA 3270 Research Unit, Marseille, France 4 Department of Research and Innovation, APHM, Timone Hospital, Support Unit for Clinical Research and Economic Evaluation, Marseille, France 5 Department of Pediatric Oncology, APHM, Timone Hospital, Marseille, France 6 Department of Pediatric Orthopaedic Surgery, APHM, Timone Hospital, Marseille, France 7 Department of Adult Orthopaedic Surgery, APHM, Nord Hospital, Marseille, France 8 Institut Albert Bonniot, U823, Grenoble, France Correspondence to: Corinne Bouvier, email: // Keywords : osteosarcoma, hippo pathway, YAP/TAZ, beta1 integrin, prognosis, Pathology Section Received : May 23, 2016 Accepted : August 01, 2016 Published : September 06, 2016 Abstract Introduction: Currently, very few studies are available concerning the mammalian Hippo pathway in bone sarcomas. YAP/TAZ transcription co-activators are key downstream effectors of this pathway and may also have oncogenic properties. Additionally, recent in-vitro experiments showed that expression of β1-integrin promoted metastasis in osteosarcomas. This study investigated the expression of YAP/TAZ and β1-integrin in human osteosarcomas. Materials and methods: We performed automated immunohistochemistry on tissue-microarrays (TMA) in which 69 conventional osteosarcomas biopsies performed prior to chemotherapy were embedded. Cellular localization and semi-quantitative analysis of each immunostain was performed using Immunoreactive Score (IRS) and correlated to clinico-pathological data. Results: Cytoplasmic expression of β1-integrin was noted in 54/59 osteosarcomas (92%), with 33/59 cases (56%) displaying membranous staining. YAP/TAZ was expressed in 27/45 osteosarcomas (60%), with 14 cases (31%) showing cytoplasmic expression while 13 other cases (28%) displayed nuclear expression. No link was found between YAP/TAZ or β1-integrin expression and response to chemotherapy. In univariate analysis, YAP/TAZ immunoreactive score was pejoratively correlated with overall survival ( p = 0.01). Expression of β1-integrin on cell membrane was also pejorative for OS ( p = 0.045). In multivariate analysis, YAP/TAZ nuclear expression was an independent prognostic factor for PFS ( p = 0.035). Conclusion: this study indicates that β1-integrin and YAP/TAZ proteins are linked to prognosis and therefore could be therapeutic targets in conventional osteosarcomas.