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: 5.27). 11/2010; 32(3):389-98. DOI: 10.1093/carcin/bgq254
Source: PubMed

ABSTRACT 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.

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Available from: Ken-ichi Kozaki, Apr 17, 2014
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    • "Yap1 is known to be involved in cell proliferation, epithelial-to-mesenchymal transition, invasion, and metastasis. Notably, recurrent amplifications of Yap1 locus 11q22 have been observed in liver carcinoma , oral squamous cell carcinomas, medulloblastomas, and esophageal cancer (Zender et al., 2006; Snijders et al., 2005; Fernandez-L et al., 2009; Muramatsu et al., 2011). Our findings indicate that Yap1 is sufficient for driving PDAC recurrence upon Kras withdrawal in the iKras model, previously characterized for its dependence on oncogenic Kras signaling for tumor initiation, progression, and maintenance. "
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    ABSTRACT: Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible Kras(G12D)-driven mouse model of PDAC has established a critical role for sustained Kras(G12D) expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of Kras(G12D)-independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras(G12D)-independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.
    Cell 06/2014; 158(1). DOI:10.1016/j.cell.2014.06.003 · 33.12 Impact Factor
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    • "The expression and role of YAP in cancer are cell-type-and/or cellular-context-dependent (Strano et al. 2005, Harvey et al. 2013). Amplification of the YAP gene locus at 11q22 is found in hepatocellular carcinoma, breast cancer, oral squamous cell carcinomas, medulloblastomas, and esophageal squamous cell carcinomas (Snijders et al. 2005, Overholtzer et al. 2006, Zender et al. 2006, Fernandez et al. 2009, Muramatsu et al. 2011). In addition, overexpression and nuclear localization of YAP protein are found in colon, liver, lung, ovarian, and prostate cancers (Zender et al. 2006, Zhao et al. 2007, Steinhardt et al. 2008, Yu & Guan 2013). "
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    ABSTRACT: The Hippo signaling pathway has been implicated as a conserved regulator of organ size in both Drosophila and mammals. Yes associated protein (YAP), the central component of the Hippo signaling cascade, functions as an oncogene in several malignancies. Ovarian granulosa cell tumors (GCT) are characterized by enlargement of ovary, excess production of estrogen, high frequency of recurrence and potential of malignancy and metastasis. Whether the Hippo pathway plays a role in the pathogenesis of GCT is unknown. This study was conducted to examine the expression of YAP in human adult GCTs and to determine the role of YAP in the proliferation and steroidogenesis of GCT cells. Compared with age-matched normal human ovaries, GCT tissues exhibited higher levels of YAP expression. YAP protein was predominantly expressed in the nucleus of tumor cells, whereas the non-tumor ovarian stromal cells expressed very low levels of YAP. YAP was also expressed in cultured primary human granulosa cells and in KGN and COV434 GCT cell lines. siRNA-mediated knockdown of YAP in KGN cells resulted in a significant reduction in cell proliferation (P<0.001). Conversely, overexpression of wild-type YAP or a constitutively active YAP mutant resulted in a significant increase in KGN cell proliferation and migration. Moreover, YAP knockdown reduced FSH-induced aromatase (CYP19A1) protein expression and estrogen production in KGN cells. These results demonstrate that YAP plays an important role in regulating GCT cell proliferation, migration and steroidogenesis. Targeting the Hippo/YAP pathway may provide a novel therapeutic approach for GCT.
    Endocrine Related Cancer 01/2014; 21(2). DOI:10.1530/ERC-13-0339 · 4.91 Impact Factor
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    ABSTRACT: The Hippo pathway regulates cell proliferation and apoptosis through the Yes-associated protein (YAP) transcriptional activator. YAP has a well-described role in promoting cell proliferation and survival, but the precise mechanisms and transcriptional targets that underlie these properties are still unclear and likely context-dependent. We found, using siRNA-mediated knockdown, that YAP is required for proliferation in endothelial cells but not HeLa cells. Specifically, YAP is required for S-phase entry and its absence causes cells to accumulate in G1. Microarray analysis suggests that YAP mediates this effect by regulating the transcription of genes involved in the assembly and/or firing of replication origins and homologous recombination of DNA. These findings thus provide insight into the molecular mechanisms by which YAP regulates cell cycle progression.
    PLoS ONE 01/2015; 10(1):e0117522. DOI:10.1371/journal.pone.0117522 · 3.53 Impact Factor
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