Abstract
IntroductionCurrently, 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 methodsWe 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.ResultsCytoplasmic 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).Conclusionthis study indicates that β1-integrin and YAP/TAZ proteins are linked to prognosis and therefore could be therapeutic targets in conventional osteosarcomas.
Highlights
Very few studies are available concerning the mammalian Hippo pathway in bone sarcomas
Few years ago it was suggested that the Hippo signaling pathway might play a role in osteogenic differentiation: expression of an active TAZ mutant enhanced RUNX2-driven gene expression [22, 23] while knockdown of TAZ in mesenchymal stem cells (MSCs) inhibited osteogenesis when the cells were cultured under conditions favoring osteoblast differentiation
When an activated YAP mutant was overexpressed in MSCs, osteogenic differentiation was promoted over adipogenic differentiation even when cells were cultured under conditions favoring adipogenesis [24]
Summary
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 have oncogenic properties. This study investigated the expression of YAP/TAZ and β1-integrin in human osteosarcomas. YAP (Yes-Associated Protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) are downstream effectors of the hippo pathway and serves as transcriptional co-activators. This pathway is well conserved during evolution probably owing to its involvement in development: the hippo pathway is necessary to regulate the size of organs, tissue homeostasis and tissue repair in mammals and drosophila [1]. The binding of YAP/TAZ along with other transcriptional factors on specific sequences (which are called TEA domain-containing sequence-specific transcription factors, namely TEADs) induces proliferation, self-renewal, differentiation and survival of the cells [2]
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