YAP is a candidate oncogene for esophageal squamous cell carcinoma

Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University,Bunkyo-ku, Tokyo 113-8510, Japan.
Carcinogenesis (Impact Factor: 5.33). 11/2010; 32(3):389-98. DOI: 10.1093/carcin/bgq254
Source: PubMed


Yes-associated protein (YAP), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene located at chromosome 11q22. Since we previously reported amplification of 11q22 region in esophageal squamous cell carcinoma (ESCC), in this study we focused on the clinical significance and biological functions of YAP in this tumor. Frequent overexpression of YAP protein was observed in ESCC cells including those with a robust amplicon at position 11q22. Overexpression of the YAP protein was frequently detected in primary tumors of ESCC as well. Patients with YAP-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors, and YAP positivity was independently associated with a worse outcome in the multivariate analysis. Further analyses in cells in which YAP was either overexpressed or depleted confirmed that cell proliferation was promoted in a YAP isoform-independent but YAP expression level-dependent manner. YAP depletion inhibited cell proliferation mainly in the G(0)-G(1) phase and induced an increase in CDKN1A/p21 transcription but a decrease in BIRC5/survivin transcription. Our results indicate that YAP is a putative oncogene in ESCC and it represents a potential diagnostic and therapeutic target.


Available from: Ken-ichi Kozaki, Apr 17, 2014
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    • "Several studies define YAP as an oncogene. For example , the amplification of the YAP gene locus at 11q22 is found in several types of cancers (Snijders et al, 2005; Overholtzer et al, 2006; Zender et al, 2006; Fernandez et al, 2009; Kang et al, 2011; Muramatsu et al, 2011). Overexpression and nuclear localization of the YAP protein has been noted in colon, liver, lung, ovarian, and prostate cancers (Snijders et al, 2005; Zhao et al, 2007; Steinhardt et al, 2008; Zhang et al, 2011; Yu & Guan, 2013; He et al, 2015). "
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    ABSTRACT: The Hippo signaling pathway controls organ size and tumorigene-sis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-a and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-a, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed-forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer.
    EMBO Molecular Medicine 09/2015; 7(11):e201404976. DOI:10.15252/emmm.201404976 · 8.67 Impact Factor
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    • "Using immunohistochemistry, YAP has been found to be either strongly expressed or highly localized to the nucleus (where it is active in gene transcription) in human cancers compared with normal tissue. Increased expression and/or nuclear accumulation of YAP has been reported in a wide array of human cancers including HCC, prostate cancer, colorectal carcinoma (CRC), NSCLC, ovarian cancer, ccRCC, pancreatic carcinoma, esophageal squamous cell carcinoma, urothelial carcinoma of the bladder, and skin basal cell carcinoma (Additional file 1: Table S1) [34,61-63,67,71,72,76,83-87]. Notably, expression or nuclear localization of YAP is associated with poorer tumor differentiation and higher-grade tumors [76,86]. "
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    ABSTRACT: Understanding the molecular nature of human cancer is essential to the development of effective and personalized therapies. Several different molecular signal transduction pathways drive tumorigenesis when deregulated and respond to different types of therapeutic interventions. The Hippo signaling pathway has been demonstrated to play a central role in the regulation of tissue and organ size during development. The deregulation of Hippo signaling leads to a concurrent combination of uncontrolled cellular proliferation and inhibition of apoptosis, two key hallmarks in cancer development. The molecular nature of this pathway was first uncovered in Drosophila melanogaster through genetic screens to identify regulators of cell growth and cell division. The pathway is strongly conserved in humans, rendering Drosophila a suitable and efficient model system to better understand the molecular nature of this pathway. In the present study, we review the current understanding of the molecular mechanism and clinical impact of the Hippo pathway. Current studies have demonstrated that a variety of deregulated molecules can alter Hippo signaling, leading to the constitutive activation of the transcriptional activator YAP or its paralog TAZ. Additionally, the Hippo pathway integrates inputs from a number of growth signaling pathways, positioning the Hippo pathway in a central role in the regulation of tissue size. Importantly, deregulated Hippo signaling is frequently observed in human cancers. YAP is commonly activated in a number of in vitro and in vivo models of tumorigenesis, as well as a number of human cancers. The common activation of YAP in many different tumor types provides an attractive target for potential therapeutic intervention.
    Clinical and Translational Medicine 07/2014; 3(1):25. DOI:10.1186/2001-1326-3-25
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    • "Inhibition of cell proliferation in response to knockdown of YAP expression is associated with an increase of cells in G0/G1 phase of the cell cycle and a decrease of cells in S phase. Consistent with our results, previous reports have demonstrated that altered expression of the Hippo pathway, including YAP, alters cell cycle check point mechanisms [22], [45], [46]. "
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    ABSTRACT: Background Yes-associated protein (YAP) is a transcriptional co-activator and regulates cell proliferation and apoptosis. We investigated the clinical and biological significance of YAP in endometrial cancer (EMCA). Methods YAP expression in 150 primary tumor tissues from patients with EMCA was evaluated by immunohistochemistry and its association with clinicopathological data was assessed. The biological functions of YAP were determined in EMCA cell lines through knockdown/overexpression of YAP. The role of YAP in modulating radiation sensitivity was also investigated in EMCA cells. Results Increased nuclear YAP expression was significantly associated with higher grade, stage, lympho-vascular space invasion, postoperative recurrence/metastasis and overall survival in estrogen mediated EMCA, called type 1 cancer (p = 0.019, = 0.028, = 0.0008, = 0.046 and = 0.015, respectively). In multivariate analysis, nuclear YAP expression was confirmed as an independent prognostic factor for overall survival in type 1 EMCA. YAP knockdown by siRNA resulted in a significant decrease in cell proliferation (p<0.05), anchorage-dependent growth (p = 0.015) and migration/invasion (p<0.05), and a significant increase in the number of cells in G0/G1 phase (p = 0.002). Conversely, YAP overexpression promoted cell proliferation. Clonogenic assay demonstrated enhanced radiosensitivity by approximately 36% in YAP inhibited cells. Conclusions Since YAP functions as a transcriptional co-activator, its differential localization in the nucleus of cancer cells and subsequent impact on cell proliferation could have important consequences with respect to its role as an oncogene in EMCA. Nuclear YAP expression could be useful as a prognostic indicator or therapeutic target and predict radiation sensitivity in patients with EMCA.
    PLoS ONE 06/2014; 9(6):e100974. DOI:10.1371/journal.pone.0100974 · 3.23 Impact Factor
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