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Prognostic significance of a component of the Hippo pathway, TAZ, in human uterine endometrioid adenocarcinoma.

ABSTRACT: Transcriptional coactivator with PDZ-binding motif (TAZ) is a crucial component of the Hippo tumor suppressor pathway, interacting with transcriptional factors to regulate cell proliferation, apoptosis and tumorigenesis. TAZ and its paralog, Yes-associated protein (YAP), are activated at high frequencies during the progression towards malignancy in various tumors. Recently, YAP has been identified to modulate oncogenic features in endometrial adenocarcinoma, and it has also been reported that the nuclear expression of YAP is correlated with the poorly-differentiated form of endometrioid adenocarcinoma. In contrast to YAP, no studies have investigated TAZ expression in endometrioid adenocarcinoma. In the present study, TAZ expression was immunohistochemically examined in 55 clinical samples of endometrioid adenocarcinoma, and the clinical implications were evaluated. The results demonstrated that TAZ was located primarily in the cell nuclei, and that high TAZ expression was significantly correlated with high tumor-factor (P=0.024), stage (P=0.041) and histological grade (P=0.001), lymph node metastasis (P=0.046), recurrence (P=0.002) and a poor prognosis (P=0.007). Furthermore, univariate analysis identified that high TAZ expression was a poor prognostic factor for overall and disease-free survival. To the best of our knowledge, the present case is the first to report the clinical implications of TAZ in endometrioid adenocarcinoma of the uterus. TAZ may become a marker of a poor prognosis in endometrioid adenocarcinoma.

SUBMITTER: Zhan M

PROVIDER: S-EPMC4887927 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Prognostic significance of a component of the Hippo pathway, TAZ, in human uterine endometrioid adenocarcinoma.

Zhan Maosheng M Ikeda Jun-Ichiro JI Wada Naoki N Hori Yumiko Y Nojima Satoshi S Tahara Shin-Ichiro SI Ueda Yutaka Y Yoshino Kiyoshi K Kimura Tadashi T Morii Eiichi E

Oncology letters 20160420 6

Transcriptional coactivator with PDZ-binding motif (TAZ) is a crucial component of the Hippo tumor suppressor pathway, interacting with transcriptional factors to regulate cell proliferation, apoptosis and tumorigenesis. TAZ and its paralog, Yes-associated protein (YAP), are activated at high frequencies during the progression towards malignancy in various tumors. Recently, YAP has been identified to modulate oncogenic features in endometrial adenocarcinoma, and it has also been reported that th ...[more]

PMID: 27284362

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Project description:BackgroundIntrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver tumor with increasing incidence worldwide, dismal prognosis, and few therapeutic options. Mounting evidence underlines the role of the Hippo pathway in this disease; however, the molecular mechanisms whereby the Hippo cascade contributes to cholangiocarcinogenesis remain poorly defined.MethodsWe established novel iCCA mouse models via hydrodynamic transfection of an activated form of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, either alone or combined with the myristoylated AKT (myr-AKT) protooncogene, in the mouse liver. Hematoxylin and eosin staining, immunohistochemistry, electron microscopy, and quantitative real-time RT-PCR were applied to characterize the models. In addition, in vitro cell line studies were conducted to address the growth-promoting roles of TAZ and its paralog YAP.ResultsOverexpression of TAZ in the mouse liver triggered iCCA development with very low incidence and long latency. In contrast, co-expression of TAZ and myr-AKT dramatically increased tumor frequency and accelerated cancer formation in mice, with 100% iCCA incidence and high tumor burden by 10 weeks post hydrodynamic injection. AKT/TAZ tumors faithfully recapitulated many of the histomolecular features of human iCCA. At the molecular level, the development of the cholangiocellular lesions depended on the binding of TAZ to TEAD transcription factors. In addition, inhibition of the Notch pathway did not hamper carcinogenesis but suppressed the cholangiocellular phenotype of AKT/TAZ tumors. Also, knockdown of YAP, the TAZ paralog, delayed cholangiocarcinogenesis in AKT/TAZ mice without affecting the tumor phenotype. Furthermore, human preinvasive and invasive iCCAs and mixed hepatocellular carcinoma/iCCA displayed widespread TAZ activation and downregulation of the mechanisms protecting TAZ from proteolysis.ConclusionsOverall, the present data underscore the crucial role of TAZ in cholangiocarcinogenesis.

Dataset Information

Prognostic significance of a component of the Hippo pathway, TAZ, in human uterine endometrioid adenocarcinoma.

Publications

Prognostic significance of a component of the Hippo pathway, TAZ, in human uterine endometrioid adenocarcinoma.

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