Advertisement

Medical Oncology

, 31:966 | Cite as

Overexpression of Dickkopf-1 predicts poor prognosis for patients with hepatocellular carcinoma after orthotopic liver transplantation by promoting cancer metastasis and recurrence

  • Yan Huang
  • Xinrong Yang
  • Fengbo Zhao
  • Qiujin Shen
  • Zhiwei Wang
  • Xiufang Lv
  • Baoying Hu
  • Bin Yu
  • Jia FanEmail author
  • Wenxin QinEmail author
Original Paper

Abstract

Our previous data had shown that Dickkopf-1 (DKK1) combined with β-catenin was a novel prognostic predictor for hepatocellular carcinoma (HCC) patients. However, the role and mechanism of DKK1 in HCC recurrence or metastasis remain poorly understand. This study was to assess the role of DKK1 in tumor metastasis for patients with hepatocellular carcinoma after orthotopic liver transplantation (OLT). The expression of DKK1 protein was detected in hepatic cell lines, HCC cell lines, and HCC patients after OLT with different potential of metastasis. After DKK1 expression in the HCCLM3 cells was downregulated by siRNA-mediated approach, the role of DKK1 in cell invasion and metastasis was investigated. cDNA genechip was used to analyze the differential expressed genes related with DKK1 in two pairs of HCC cells. The prognostic significance of DKK1 was further assessed by Kaplan–Meier and Cox regression analyses in 148 HCC patients after OLT. The expression of DKK1 protein was higher in the high-invasive HCC cells and HCC patients of the disease recurrence group. With the downregulation of DKK1, HCCLM3 cells showed decreased aggressiveness in vitro and lower metastatic ability in vivo. DKK1 could regulate many genes involved in biological processes and pathways related with tumor progression. Furthermore, DKK1 overexpression correlated with tumor microvessel density in clinical HCC samples. Multivariate analysis revealed that DKK1 was an independent prognostic indicator for overall survival and cumulative recurrence in this cohort of HCC patients post-OLT. Collectively, overexpression of DKK1 was implicated in invasion/metastasis of HCC after OLT and DKK1 overexpression may be potential molecular therapeutic targets for liver cancer.

Keywords

DKK1 Invasion Metastasis Prognosis HCC OLT 

Notes

Acknowledgments

This study was funded by the National Key Basic Research Program of China (2009CB521803), the National Key Sci-Tech Special Projects of Infectious Diseases (2012ZX10002011-004), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Project of the State Key Laboratory of Oncogenes and Related Genes (90-10-04).

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300.PubMedCrossRefGoogle Scholar
  2. 2.
    Clavien P-A, Lesurtel M, Bossuyt PMM, Gores GJ, Langer B, Perrier A, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 2012;13(1):E11–22.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Rahbari NN, Mehrabi A, Mollberg NM, Mueller SA, Koch M, Buechler MW, et al. Hepatocellular carcinoma current management and perspectives for the future. Ann Surg. 2011;253(3):453–69.PubMedCrossRefGoogle Scholar
  4. 4.
    Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology. 2011;140(5):1410–26.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, Niehrs C. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature. 1998;391(6665):357–62.PubMedCrossRefGoogle Scholar
  6. 6.
    Fedi P, Bafico A, Nieto Soria A, Burgess WH, Miki T, Bottaro DP, et al. Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling. J Biol Chem. 1999;274(27):19465–72.PubMedCrossRefGoogle Scholar
  7. 7.
    Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127(3):469–80.PubMedCrossRefGoogle Scholar
  8. 8.
    Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochimica Et Biophysica Acta-Reviews on Cancer. 2003;1653(1):1–24.CrossRefGoogle Scholar
  9. 9.
    MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17(1):9–26.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, Espada J, et al. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene. 2006;25(29):4116–21.PubMedCrossRefGoogle Scholar
  11. 11.
    Sato H, Suzuki H, Toyota M, Nojima M, Maruyama R, Sasaki S, et al. Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. Carcinogenesis. 2007;28(12):2459–66.PubMedCrossRefGoogle Scholar
  12. 12.
    Kuphal S, Lodermeyer S, Bataille F, Schuierer M, Hoang BH, Bosserhoff AK. Expression of Dickkopf genes is strongly reduced in malignant melanoma. Oncogene. 2006;25(36):5027–36.PubMedCrossRefGoogle Scholar
  13. 13.
    Gonzalez-Sancho JM, Aguilera O, Garcia JM, Pendas-Franco N, Pena C, Cal S, et al. The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene. 2005;24(6):1098–103.PubMedCrossRefGoogle Scholar
  14. 14.
    Koch A, Waha A, Hartmann W, Hrychyk A, Schuller U, Waha A, et al. Elevated expression of Wnt antagonists is a common event in hepatoblastomas. Clin Cancer Res. 2005;11(12):4295–304.PubMedCrossRefGoogle Scholar
  15. 15.
    Yamabuki T, Takano A, Hayama S, Ishikawa N, Kato T, Miyamoto M, et al. Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas. Cancer Res. 2007;67(6):2517–25.PubMedCrossRefGoogle Scholar
  16. 16.
    Voorzanger-Rousselot N, Goehrig D, Journe F, Doriath V, Body JJ, Clezardin P, et al. Increased Dickkopf-1 expression in breast cancer bone metastases. Br J Cancer. 2007;97(7):964–70.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Hall CL, Kang S, MacDougald OA, Keller ET. Role of Wnts in prostate cancer bone metastases. J Cell Biochem. 2006;97(4):661–72.PubMedCrossRefGoogle Scholar
  18. 18.
    Takahashi N, Fukushima T, Yorita K, Tanaka H, Chijiiwa K, Kataoka H. Dickkopf-1 is overexpressed in human pancreatic ductal adenocarcinoma cells and is involved in invasive growth. Int J Cancer. 2010;126(7):1611–20.PubMedGoogle Scholar
  19. 19.
    Menezes ME, Devine DJ, Shevde LA, Samant RS. Dickkopf1: a tumor suppressor or metastasis promoter? Int J Cancer. 2012;130(7):1477–83.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Yu B, Yang X, Xu Y, Yao G, Shu H, Lin B, et al. Elevated expression of DKK1 is associated with cytoplasmic/nuclear beta-catenin accumulation and poor prognosis in hepatocellular carcinomas. J Hepatol. 2009;50(5):948–57.PubMedCrossRefGoogle Scholar
  21. 21.
    Chen L, Li M, Li Q, Wang CJ, Xie SQ. DKK1 promotes hepatocellular carcinoma cell migration and invasion through beta-catenin/MMP7 signaling pathway. Mol Cancer. 2013;12:157.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Li Y, Tian B, Yang J, Zhao L, Wu X, Ye SL, et al. Stepwise metastatic human hepatocellular carcinoma cell model system with multiple metastatic potentials established through consecutive in vivo selection and studies on metastatic characteristics. J Cancer Res Clin Oncol. 2004;130(8):460–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Marsh JW, Dvorchik I, Bonham CA, Iwatsuki S. Is the pathologic TNM staging system for patients with hepatoma predictive of outcome? Cancer. 2000;88(3):538–43.PubMedCrossRefGoogle Scholar
  24. 24.
    Ke AW, Shi GM, Zhou J, Wu FZ, Ding ZB, Hu MY, et al. Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology. 2009;49(2):491–503.PubMedCrossRefGoogle Scholar
  25. 25.
    Li JC, Yang XR, Sun HX, Xu Y, Zhou J, Qiu SJ, et al. Up-regulation of Kruppel-like factor 8 promotes tumor invasion and indicates poor prognosis for hepatocellular carcinoma. Gastroenterology. 2010;139(6):e12 2146–57.Google Scholar
  26. 26.
    Yoo HY, Patt CH, Geschwind JF, Thuluvath PJ. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time. J Clin Oncol. 2003;21(23):4329–35.PubMedCrossRefGoogle Scholar
  27. 27.
    Shen Q, Fan J, Yang XR, Tan Y, Zhao W, Xu Y, et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Lancet Oncol. 2012;13(8):817–26.PubMedCrossRefGoogle Scholar
  28. 28.
    Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006;127(4):679–95.PubMedCrossRefGoogle Scholar
  29. 29.
    Li C, Zhang F, Zhang W, Zhang L, Huang Z, Wu P. Feasibility of (125)I brachytherapy combined with sorafenib treatment in patients with multiple lung metastases after liver transplantation for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2010;136(11):1633–40.PubMedCrossRefGoogle Scholar
  30. 30.
    Fulciniti M, Tassone P, Hideshima T, Vallet S, Nanjappa P, Ettenberg SA, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood. 2009;114(2):371–9.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Sato N, Yamabuki T, Takano A, Koinuma J, Aragaki M, Masuda K, et al. Wnt inhibitor Dickkopf-1 as a target for passive cancer immunotherapy. Cancer Res. 2010;70(13):5326–36.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Yan Huang
    • 1
    • 4
  • Xinrong Yang
    • 2
  • Fengbo Zhao
    • 1
  • Qiujin Shen
    • 3
  • Zhiwei Wang
    • 4
  • Xiufang Lv
    • 1
  • Baoying Hu
    • 1
  • Bin Yu
    • 3
    • 5
  • Jia Fan
    • 2
    Email author
  • Wenxin Qin
    • 1
    • 3
    Email author
  1. 1.Medical College of Nantong UniversityNantongChina
  2. 2.Liver Cancer Institute, Zhong Shan HospitalFudan UniversityShanghaiChina
  3. 3.State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
  4. 4.Department of General Surgery, the Affiliated HospitalNantong UniversityNantongChina
  5. 5.Jiangsu Key Laboratory of NeuroregenerationNantong UniversityNantongChina

Personalised recommendations