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


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).


CONCLUSIONS
this study indicates that β1-integrin and YAP/TAZ proteins are linked to prognosis and therefore could be therapeutic targets in conventional osteosarcomas.
Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France.|Department of Pathology, APHM, Timone Hospital, Marseille, France.
Corinne
C
Bouvier
Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France.|Department of Pathology, APHM, Timone Hospital, Marseille, France.
Nicolas
N
Macagno
Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France.
Quy
Q
Nguyen
Department of Public Health, Aix-Marseille University (AMU), Faculty of Medecine, EA 3270 Research Unit, Marseille, France.|Department of Research and Innovation, APHM, Timone Hospital, Support Unit for Clinical Research and Economic Evaluation, Marseille, France.
Anderson
A
Loundou
Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France.
Carine
C
Jiguet-Jiglaire
Department of Pediatric Oncology, APHM, Timone Hospital, Marseille, France.
Jean-Claude
JC
Gentet
Department of Pediatric Orthopaedic Surgery, APHM, Timone Hospital, Marseille, France.
Jean-Luc
JL
Jouve
Department of Adult Orthopaedic Surgery, APHM, Nord Hospital, Marseille, France.
Alexandre
A
Rochwerger
Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France.|Department of Adult Orthopaedic Surgery, APHM, Nord Hospital, Marseille, France.
Jean-Camille
JC
Mattei
Institut Albert Bonniot, U823, Grenoble, France.
Daniel
D
Bouvard
Aix-Marseille University (AMU), Faculty of Medecine, CRO2, UMR 911 (Equipe IV), Marseille, France.|Department of Pathology, APHM, Timone Hospital, Marseille, France.
Sébastien
S
Salas
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D001859:Bone Neoplasms / Q000175:diagnosis* / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D005260:Female; D000090683:Hippo Signaling Pathway; D006801:Humans; D007223:Infant; D019012:Integrin beta1 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012516:Osteosarcoma / Q000175:diagnosis* / Q000453:epidemiology; D010750:Phosphoproteins / Q000378:metabolism*; D011237:Predictive Value of Tests; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D019012:Integrin beta1; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases
Pathology Section; YAP/TAZ; beta1 integrin; hippo pathway; osteosarcoma; prognosis