Tumor Biology

, Volume 34, Issue 4, pp 2169–2174 | Cite as

Clinical and prognostic significance of Yes-associated protein in colorectal cancer

  • Yan WangEmail author
  • Chengyao Xie
  • Qingchang Li
  • Ke Xu
  • Enhua Wang
Research Article


The Hippo signaling pathway is a critical regulator of organ size control during development, and its deregulation is associated with cancers. Acting downstream of this pathway, Yes-associated protein (YAP) was implicated in tumorigenesis. The present study aimed to explore the expression patterns and clinical significance of YAP in human colorectal cancer (CRC). In addition, we investigated the relationship between YAP expression and Wnt/β-catenin pathway activation in CRC. A total of 139 cases of CRC tissues were investigated by immunohistochemistry for the expression of YAP, cyclin D1, and β-catenin. The association between YAP expression and clinicopathologic features was analyzed. Our results showed that YAP was overexpressed in 52.5 % (73/139) cases of CRC and predominantly presented in the nucleus. There was an excellent correlation between YAP expression and pTNM stage (p = 0.0024). YAP expression in CRC was significantly correlated with nodal status (p = 0.0034), tumor status (p = 0.0382), and cyclin D1 overexpression (p < 0.0001). Importantly, YAP expression was associated with short overall survival (p < 0.001). Furthermore, patients with YAP-positive and nuclear β-catenin-positive profiles had worse overall survival. Univariate and multivariate analyses revealed that YAP expression was an independent prognostic indicator of CRC (p = 0.0207). Our results indicated that YAP overexpression contributed to the tumorigenesis and played a pivotal role in the progression in CRC, and the interaction of YAP and Wnt/β-catenin pathways needs further exploration.


Yes-associated protein Colorectal cancer β-catenin Prognosis 


Conflicts of interest

No conflict of interest was disclosed in this article.


  1. 1.
    Zhao B et al. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 2010;24(9):862–74.PubMedCrossRefGoogle Scholar
  2. 2.
    Dong J et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130(6):1120–33.PubMedCrossRefGoogle Scholar
  3. 3.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.PubMedCrossRefGoogle Scholar
  4. 4.
    Huang J et al. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP. Cell. 2005;122(3):421–34.PubMedCrossRefGoogle Scholar
  5. 5.
    Wu S et al. Hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell. 2003;114(4):445–56.PubMedCrossRefGoogle Scholar
  6. 6.
    Edgar BA. From cell structure to transcription: Hippo forges a new path. Cell. 2006;124(2):267–73.PubMedCrossRefGoogle Scholar
  7. 7.
    Pan D. Hippo signaling in organ size control. Genes Dev. 2007;21(8):886–97.PubMedCrossRefGoogle Scholar
  8. 8.
    Zhao B et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007;21(21):2747–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Overholtzer M et al. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A. 2006;103(33):12405–10.PubMedCrossRefGoogle Scholar
  10. 10.
    Zender L et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell. 2006;125(7):1253–67.PubMedCrossRefGoogle Scholar
  11. 11.
    Espanel X, Sudol M. Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains. J Biol Chem. 2001;276(17):14514–23.PubMedGoogle Scholar
  12. 12.
    Howell M, Borchers C, Milgram SL. Heterogeneous nuclear ribonuclear protein U associates with YAP and regulates its co-activation of Bax transcription. J Biol Chem. 2004;279(25):26300–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Komuro A et al. WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem. 2003;278(35):33334–41.PubMedCrossRefGoogle Scholar
  14. 14.
    Strano S et al. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA damage. Mol Cell. 2005;18(4):447–59.PubMedCrossRefGoogle Scholar
  15. 15.
    Strano S et al. Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem. 2001;276(18):15164–73.PubMedCrossRefGoogle Scholar
  16. 16.
    Yagi R et al. A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J. 1999;18(9):2551–62.PubMedCrossRefGoogle Scholar
  17. 17.
    Zaidi SK et al. Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription. EMBO J. 2004;23(4):790–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Zhao B et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22(14):1962–71.PubMedCrossRefGoogle Scholar
  19. 19.
    Baldwin C et al. Multiple microalterations detected at high frequency in oral cancer. Cancer Res. 2005;65(17):7561–7.PubMedGoogle Scholar
  20. 20.
    Fernandez LA et al. YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev. 2009;23(23):2729–41.CrossRefGoogle Scholar
  21. 21.
    Modena P et al. Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics. J Clin Oncol. 2006;24(33):5223–33.PubMedCrossRefGoogle Scholar
  22. 22.
    Snijders AM et al. Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma. Oncogene. 2005;24(26):4232–42.PubMedCrossRefGoogle Scholar
  23. 23.
    Steinhardt AA et al. Expression of Yes-associated protein in common solid tumors. Hum Pathol. 2008;39(11):1582–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Wang Y et al. Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci. 2010;101(5):1279–85.PubMedCrossRefGoogle Scholar
  25. 25.
    Xu MZ et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer. 2009;115(19):4576–85.PubMedCrossRefGoogle Scholar
  26. 26.
    Camargo FD et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol. 2007;17(23):2054–60.PubMedCrossRefGoogle Scholar
  27. 27.
    Jemal A, et al. Cancer statistics. CA Cancer J Clin.2010.Google Scholar
  28. 28.
    Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008;8(5):387–98.PubMedCrossRefGoogle Scholar
  29. 29.
    Avruch J, Zhou D, Bardeesy N. YAP oncogene overexpression supercharges colon cancer proliferation. Cell Cycle. 2012;11(6):1090–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Zhou D et al. Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. Proc Natl Acad Sci U S A. 2011;108(49):E1312–20.PubMedCrossRefGoogle Scholar
  31. 31.
    Konsavage Jr WM et al. Wnt/beta-catenin signaling regulates Yes-associated protein (YAP) gene expression in colorectal carcinoma cells. J Biol Chem. 2012;287(15):11730–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Ogino S et al. A cohort study of cyclin D1 expression and prognosis in 602 colon cancer cases. Clin Cancer Res. 2009;15(13):4431–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Cao X, Pfaff SL, Gage FH. YAP regulates neural progenitor cell number via the TEA domain transcription factor. Genes Dev. 2008;22(23):3320–34.PubMedCrossRefGoogle Scholar
  34. 34.
    Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127(3):469–80.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Yan Wang
    • 1
    Email author
  • Chengyao Xie
    • 1
  • Qingchang Li
    • 1
  • Ke Xu
    • 2
  • Enhua Wang
    • 1
  1. 1.Department of Pathology, First Affiliated Hospital and College of Basic Medical SciencesChina Medical UniversityShenyangPeople’s Republic of China
  2. 2.Department of RadiologyFirst Affiliated Hospital of China Medical UniversityShenyangPeople’s Republic of China

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