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

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          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.

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          Most cited references27

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          Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP.

          The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD-YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD-YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.
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            [Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue].

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              Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.

              The heterogeneity and instability of human tumors hamper straightforward identification of cancer-causing mutations through genomic approaches alone. Herein we describe a mouse model of liver cancer initiated from progenitor cells harboring defined cancer-predisposing lesions. Genome-wide analyses of tumors in this mouse model and in human hepatocellular carcinomas revealed a recurrent amplification at mouse chromosome 9qA1, the syntenic region of human chromosome 11q22. Gene-expression analyses delineated cIAP1, a known inhibitor of apoptosis, and Yap, a transcription factor, as candidate oncogenes in the amplicon. In the genetic context of their amplification, both cIAP1 and Yap accelerated tumorigenesis and were required to sustain rapid growth of amplicon-containing tumors. Furthermore, cIAP1 and Yap cooperated to promote tumorigenesis. Our results establish a tractable model of liver cancer, identify two oncogenes that cooperate by virtue of their coamplification in the same genomic locus, and suggest an efficient strategy for the annotation of human cancer genes.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                4 October 2016
                6 September 2016
                : 7
                : 40
                : 64702-64710
                Affiliations
                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
                Author notes
                Correspondence to: Corinne Bouvier, corinne.bouvier2@ 123456ap-hm.fr
                Article
                11876
                10.18632/oncotarget.11876
                5323109
                27608849
                f8914dd7-d83c-4726-a28f-df80573d7532
                Copyright: © 2016 Bouvier et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 23 May 2016
                : 1 August 2016
                Categories
                Research Paper: Pathology

                Oncology & Radiotherapy
                osteosarcoma,hippo pathway,yap/taz,beta1 integrin,prognosis,pathology section
                Oncology & Radiotherapy
                osteosarcoma, hippo pathway, yap/taz, beta1 integrin, prognosis, pathology section

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