Introduction: Yes-associated protein 1 (YAP1), the nuclear effector of the Hippo pathway, plays an important role in many tumor entities. We evaluated staining and clinical significance of YAP1 and phosphorylated YAP1 (pYAP1) in urothelial bladder cancer (BCA). Materials and Methods: We used a tissue micorarray with samples of patients with muscle-invasive bladder cancer (MIBC, n = 192), non-muscle-invasive bladder cancer (NMIBC, n = 192) and normal urothelial bladder tissue (CTRL, n = 38) to determine the immunhistochemical staining of YAP1 and pYAP1. Cytoplasmatic and nuclear levels were evaluated. The t test was used for comparative analysis. Overall survival and progression-free survival were evaluated by Kaplan-Meier estimates and the Cox proportional hazard regression model. Results: Nuclear YAP1 as well as cytoplasmatic pYAP1 levels were higher in CTRL than in BCA, whereby both - NMIBC and MIBC - had lower levels than CTRL. Among patients with MIBC, cytoplasmatic YAP1 and pYAP1 staining decreased with advanced stage. YAP1 and pYAP1 staining did not correlate with the recurrence rate, progression-free, cancer-specific or overall survival. Conclusions: Immunhistochemical staining and subcellular localization of YAP1 and pYAP1 are different for BCA, NMIBC, MIBC and CTRL, indicating that the Hippo pathway is involved in urothelial carcinogenesis.

Keywords:
YAP1, pYAP1, Urothelial bladder cancer, Immunhistochemistry
1.
Siegel R, Ma J, Zou Z, Jemal A: Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.
2.
Advanced Bladder Cancer (ABC) Meta-Analysis Collaboration: Adjuvant chemotherapy for invasive bladder cancer (individual patient data). Cochrane Database Syst Rev 2006;2:CD006018.
3.
Diep CH, Zucker KM, Hostetter G, Watanabe A, Hu C, Munoz RM, Von Hoff DD, Han H: Down-regulation of yes associated protein 1 expression reduces cell proliferation and clonogenicity of pancreatic cancer cells. PLoS One 2012;7:e32783.
4.
Hall CA, Wang R, Miao J, Oliva E, Shen X, Wheeler T, Hilsenbeck SG, Orsulic S, Goode S: Hippo pathway effector Yap is an ovarian cancer oncogene. Cancer Res 2010;70:8517-8525.
5.
Zhao B, Lei QY, Guan KL: The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr Opin Cell Biol 2008;20:638-646.
6.
Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, Zheng P, Ye K, Chinnaiyan A, Halder G, Lai ZC, Guan KL: Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 2007;21:2747-2761.
7.
Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ, Mu D, Lucito R, Powers S, Lowe SW: Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 2006;125:1253-1267.
8.
Steinhardt AA, Gayyed MF, Klein AP, Dong J, Maitra A, Pan D, Montgomery EA, Anders RA: Expression of yes-associated protein in common solid tumors. Hum Pathol 2008;39:1582-1589.
9.
Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT, Zender L, Lowe SW, Poon RT, Luk JM: Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 2009;115:4576-4585.
10.
Edgar BA: From cell structure to transcription: Hippo forges a new path. Cell 2006;124:267-273.
11.
Harvey K, Tapon N: The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network. Nat Rev Cancer 2007;7:182-191.
12.
Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan D: Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 2007;130:1120-1133.
13.
Huang J, Wu S, Barrera J, Matthews K, Pan D: The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP. Cell 2005;122:421-434.
14.
Zhao B, Ye X, Yu J, Li L, Li W, Li S, Yu J, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, Guan KL: TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 2008;22:1962-1971.
15.
Fujii M, Toyoda T, Nakanishi H, Yatabe Y, Sato A, Matsudaira Y, Ito H, Murakami H, Kondo Y, Kondo E, Hida T, Tsujimura T, Osada H, Sekido Y: TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth. J Exp Med 2012;209:479-494.
16.
Schneider AC, Heukamp LC, Rogenhofer S, Fechner G, Bastian PJ, von Ruecker A, Müller SC, Ellinger J: Global histone H4K20 trimethylation predicts cancer-specific survival in patients with muscle-invasive bladder cancer. BJU Int 2011;108(8 pt 2):E290-E296.
17.
von der Emde L, Goltz D, Latz S, Müller SC, Kristiansen G, Ellinger J, Syring I: Prostaglandin receptors EP1-4 as a potential marker for clinical outcome in urothelial bladder cancer. Am J Cancer Res 2014;4:952-962.
18.
Liu JY, Li YH, Lin HX, Liao YJ, Mai SJ, Liu ZW, Zhang ZL, Jiang LJ, Zhang JX, Kung HF, Zeng YX, Zhou FJ, Xie D: Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder. BMC Cancer 2013;13:349.
19.
Kupershmidt I, Su QJ, Grewal A, Sundaresh S, Halperin I, Flynn J, Shekar M, Wang H, Park J, Cui W, Wall GD, Wisotzkey R, Alag S, Akhtari S, Ronaghi M: Ontology-based meta-analysis of global collections of high-throughput public data. PLoS One 2010;pii:e13066.
20.
Mengual L, Burset M, Ars E, Lozano JJ, Villavicencio H, Ribal MJ, Alcaraz A: DNA microarray expression profiling of bladder cancer allows identification of noninvasive diagnostic markers. J Urol 2009;182:741-748.
21.
Zhang Z, Furge KA, Yang XJ, Teh BT, Hansel DE: Comparative gene expression profiling analysis of urothelial carcinoma of the renal pelvis and bladder. BMC Med Genomics 2010;3:58.
22.
Kim WJ, Kim EJ, Kim SK, Kim YJ, Ha YS, Jeong P, Kim MJ, Yun SJ, Lee KM, Moon SK, Lee SC, Cha EJ, Bae SC: Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer. Mol Cancer 2010;9:3.
23.
Zhao B, Li L, Lei Q, Guan KL: The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev 2010;24:862-874.
24.
Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X: Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci 2010;101:1279-1285.
25.
Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA: Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A 2006;103:12405-12410.
26.
Yuan M, Tomlinson V, Lara R, Holliday D, Chelala C, Harada T, Gangeswaran R, Manson-Bishop C, Smith P, Danovi SA, Pardo O, Crook T, Mein CA, Lemoine NR, Jones LJ, Basu S: Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ 2008;15:1752-1759.
27.
Snijders AM, Schmidt BL, Fridlyand J, Dekker N, Pinkel D, Jordan RC, Albertson DG: Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma. Oncogene 2005;24:4232-4242.
28.
Fernandez-L A, Northcott PA, Dalton J, Fraga C, Ellison D, Angers S, Taylor MD, Kenney AM: YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates sonic hedgehog-driven neural precursor proliferation. Genes Dev 2009;23:2729-2741.
29.
Strano S, Monti O, Pediconi N, Baccarini A, Fontemaggi G, Lapi E, Mantovani F, Damalas A, Citro G, Sacchi A, Del Sal G, Levrero M, Blandino G: The transcriptional coactivator yes-associated protein drives p73 gene-target specificity in response to DNA Damage. Mol Cell 2005;18:447-459.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.