Advertisement

Tumor Biology

, Volume 37, Issue 10, pp 13499–13508 | Cite as

Clinicopathological and prognostic significance of Yes-associated protein expression in hepatocellular carcinoma and hepatic cholangiocarcinoma

  • Hao Wu
  • Yan Liu
  • Xiao-Wei Jiang
  • Wen-Fang Li
  • Gang Guo
  • Jian-Ping Gong
  • Xiong Ding
Original Article

Abstract

Hepatocellular carcinoma (HCC) and hepatic cholangiocarcinoma (CC) are the most aggressive malignancies with a poor prognosis in humans, and hepatic cholangiocarcinoma (CC) exhibits greater malignant behaviour. Yes-associated protein (YAP) is an important downstream target of the Hippo signalling pathway. As an oncogene, it plays a vital role in the occurrence and development of tumours. Our study focuses on the clinical significance of YAP protein expression in HCC and CC. Furthermore, we sought to explore the different survival rates between HCC and CC. A total of 137 patients with HCC and 122 with CC after resection were evaluated by immunohistochemistry for the expression of YAP. Our results showed that positive expression rates of YAP were more frequently noted in CC 67.2 % (82/122) than in HCC 56.9 % (78/137) (P = 0.024). High YAP expression in HCC and CC was significantly associated with tumour size (P < 0.001 and P = 0.019, respectively), liver cirrhosis (P = 0.002 and P = 0.009, respectively), vascular invasion (P = 0.047 and P = 0.018, respectively), multiplicity (P = 0.019 and P = 0.015, respectively), and intrahepatic metastasis (P = 0.015 and P = 0.047, respectively). Importantly, recurrence-free survival and disease-specific survival rates were lower in CC with high YAP expression than in HCC with high YAP expression (P < 0.001 and P < 0.001, respectively). Overall, high YAP expression was more frequently found in CC than in HCC, and YAP overexpression was associated with poor survival rates in patients with HCC and CC. Targeting YAP treatment requires further prospective investigations in larger patient populations.

Keywords

Hepatocellular carcinoma Hepatic cholangiocarcinoma Yes-associated protein(YAP) Immunohistochemistry 

Notes

Acknowledgments

This research was funded by the National Natural Science Foundation of China, projects No 81272570 and the Health Bureau of Chongqing City, projects No 2015ZDXM012.

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Media centre. Title of subordinate document. In: Cancer. 2015. http://www.who.int/mediacentre/factsheets/fs297/en/. Accessed 18 Feb 2015.
  2. 2.
    Koh KC, Lee H, Choi MS, et al. Clinicopathologic features and prognosis of combined hepatocellular cholangiocarcinoma. Am J Surg. 2005;189:120–5.CrossRefPubMedGoogle Scholar
  3. 3.
    Wang J, Wang F, Kessinger A. Outcome of combined hepatocellular and cholangiocarcinoma of the liver. Journal of Oncology Volume. 2010. doi: 10.1155/2010/917356.Google Scholar
  4. 4.
    Bosetti C, Turati F, Vecchia CL. Hepatocellular carcinoma epidemiology. Best Pract Res Clin Gastroenterol. 2014;28:753–70.CrossRefPubMedGoogle Scholar
  5. 5.
    Ertle JM, Heider D, Wichert M, Keller B, Kueper R, Hilgard P, et al. A combination of alpha-fetoprotein and des-gamma-carboxy prothrombin is superior in detection of hepatocellular carcinoma. Digestion. 2013;87:121–31.CrossRefPubMedGoogle Scholar
  6. 6.
    Wang XM, Yang LY, Guo L, Fan C, Wu F. p53-induced RING-H2 protein, a novel marker for poor survival in hepatocellular carcinoma after hepatic resection. Cancer. 2009;115:4554–63.CrossRefPubMedGoogle Scholar
  7. 7.
    Johnson R, Halder G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat Rev Drug Discov. 2013;13:63–79.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13:246–57.CrossRefPubMedGoogle Scholar
  9. 9.
    Huang J, Wu S, Barrera 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.CrossRefPubMedGoogle Scholar
  10. 10.
    Edgar BA. From cell structure to transcription: Hippo forges a new path. Cell. 2006;124(2):267–73.CrossRefPubMedGoogle Scholar
  11. 11.
    Kim JE, Finlay GJ, Baguley BC. The role of the hippo pathway in melanocytes and melanoma. Front Oncol. 2013;3:123.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Komuro A, Nagai M, Navin NE, 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.CrossRefPubMedGoogle Scholar
  13. 13.
    Nallet-Staub F, Marsaud V, Li L, et al. Pro-invasive activity of the Hippo pathway effectors YAP and TAZ in cutaneous melanoma. J Invest Dermatol. 2014;134:123–32.CrossRefPubMedGoogle Scholar
  14. 14.
    Morvaridi S, Dhall D, Greene M, et al. Role of YAP and TAZ in pancreatic ductal adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis. Scientific Reports. 2015;5:16759.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zender L, Spector MS, Xue W, et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell. 2006;125:1253–67.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    He C, Mao D, Hua G, et al. The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. EMBO Molecular Medicine. 2015;7(11):1426–49.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Maugeri-Saccà M, Barba M, Pizzuti L, et al. The Hippo transducers TAZ and YAP in breast cancer: oncogenic activities and clinical implications. Expert Rev Mol Med. 2015. doi: 10.1017/erm.2015.12. PubMedGoogle Scholar
  18. 18.
    Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X. Overexpression of yesassociated protein contributes to progression and poor prognosis of nonsmall-cell lung cancer. Cancer Sci. 2010;101:1279–85.CrossRefPubMedGoogle Scholar
  19. 19.
    Kang W, Tong JH, Chan AW. Yes-associated protein 1 exhibits oncogenic property in gastric cancer and its nuclear accumulation associates with poor prognosis. Clin Cancer Res. 2011;17:2130–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Avruch J, Zhou D, Bardeesy N. YAP oncogene overexpression supercharges colon cancer proliferation. Cell Cycle. 2012;11:1090–6.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kim M, Kim T, Johnson RL, et al. Transcriptional Co-repressor function of the Hippo pathway transducers YAP and TAZ. Cell Rep. 2015;11(2):270–82.CrossRefPubMedGoogle Scholar
  22. 22.
    Wang Y, Xie C, Li Q, et al. Clinical and prognostic significance of Yes-associated protein in colorectal cancer. Tumor Biol. 2013;34:2169–74.CrossRefGoogle Scholar
  23. 23.
    Zhao B, Wei X, Li W, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007;21:2747–61.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Xu MZ, Yao TJ, Lee NP, et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer. 2009;115:4576–85.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Li H, Wang S, Wang G, et al. Yes-associated protein expression is a predictive marker for recurrence of hepatocellular carcinoma after liver transplantation. Dig Surg. 2014;31(6):468–78.CrossRefPubMedGoogle Scholar
  26. 26.
    Yang X, Xu T. Molecular mechanism of size control in development and human diseases. Cell Res. 2011;21:715–29.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Dong J, Feldmann G, Huang J, Comerford SA, et al. Elucidation of a universal size-control mechanism in drosophila and mammals. Cell. 2007;130(6):1120–33.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zhao B, Ye X, Yu J, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22:1962–71.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hen L, Loh PG, Song H. Structural and functional insights into the TEAD-YAP complex in the hippo signaling pathway. Protein Cell. 2010;1:1073–83.CrossRefGoogle Scholar
  30. 30.
    Hao Y, Chun A, Cheung K, et al. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem. 2008;283:5496–509.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Hao Wu
    • 1
  • Yan Liu
    • 2
  • Xiao-Wei Jiang
    • 3
  • Wen-Fang Li
    • 4
  • Gang Guo
    • 5
  • Jian-Ping Gong
    • 1
  • Xiong Ding
    • 1
  1. 1.Department of Hepatobiliary SurgeryThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
  2. 2.Department of GastroenterologyThe Fifth people’s Hospital of ChengduChengduChina
  3. 3.Department of General SurgeryThe Fifth people’s Hospital of ChongqingChongqingChina
  4. 4.Department of General SurgeryThe Taihe Hospital Affiliated to Hubei Medical UniversityShiyanChina
  5. 5.Laboratory of PathologyWest China Hospital of Sichuan UniversityChengduChina

Personalised recommendations