Tumor Biology

, Volume 37, Issue 1, pp 999–1008 | Cite as

Diagnostic and prognostic significance of secretory clusterin expression in patients with hepatocellular carcinoma

  • Wenjie Zheng
  • Min Yao
  • Wenli Sai
  • Qi Qian
  • Liuhong Pan
  • Liwei Qiu
  • Jianfei Huang
  • Wei Wu
  • Dengfu Yao
Original Article


The upregulation of secretory clusterin (sCLU) is associated with tumor progression by contributing to angiogenesis, chemo-resistance, cell survival, and metastasis. However, its diagnostic or prognostic values for hepatocellular carcinoma (HCC) still remain to be clarified. The average serum sCLU level analyzed by an enzyme-linked immunosorbent assay was significantly higher (P < 0.001) in HCC patients than that in any of cases with cirrhosis, chronic hepatitis, or healthy control. The area under receiver operating characteristic curve and diagnostic sensitivity were 0.75 and 74.7 % in sCLU, and 0.74 and 58.7 % in α-fetoprotein (AFP), respectively. The combining detections of sCLU and AFP rose up to 90.7 % for HCC diagnosis. In liver, sCLU by immunohistochemistry was significantly higher (P < 0.001) in the HCC (77.3 %) group than that in their para-cancerous group (33.3 %). Abnormal serum or tissue sCLU expression was closely associated with tumor–node–metastasis (TNM) classification of malignant tumors and lymph node metastasis, as an independent prognosis factor (hazard ratio, 2.287; 95 % confidence interval, 1.044–5.007; P = 0.039), and higher sCLU expression significantly correlated (χ 2 = 4.252, P = 0.039) with poor survival of HCC patients analyzed by multivariate Cox regression or Kaplan–Meier method, suggesting that abnormal sCLU expression associated with tumor progression could be a potential diagnostic and prognostic biomarker for HCC.


Hepatocellular carcinoma Clusterin Diagnosis Prognosis 







Enzyme-linked immunosorbent assay


Hepatitis B virus


Hepatocellular carcinoma


Hepatitis C virus




Overall survival


Tissue microarray



This work was supported by grants-in-aid from some Projects of the Chinese National Natural Science Foundation (81200634), the Nantong Society Development (HS2014078), the Jiangsu Health Projects (BL2012053, YY-028, K201102, and WSN-078), the Priority Academic Program Development of Jiangsu (PADA), and the International S&T Cooperation Program of China (2013DFA32150).

Conflicts of interest



  1. 1.
    Knudsen ES, Gopal P, Singal AG. The changing landscape of hepatocellular carcinoma: etiology, genetics, and therapy. Am J Pathol. 2014;184(3):574–83.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245–55.CrossRefPubMedGoogle Scholar
  3. 3.
    Kawano Y, Sasaki A, Kai S, Endo Y, Iwaki K, Uchida H, et al. Prognosis of patients with intra-hepatic recurrence after hepatic resection for hepatocellular carcinoma: a retrospective study. Eur J Surg Oncol. 2009;35(2):174–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Blaschuk O, Burdzy K, Fritz IB. Purification and characterization of a cell- aggregating factor (clusterin), the major glycoprotein in ram rete testis fluid. J Biol Chem. 1983;258(12):7714–20.PubMedGoogle Scholar
  5. 5.
    Trougakos IP, Djeu JY, Gonos ES, Boothman DA. Advances and challenges in basic and translational research on clusterin. Cancer Res. 2009;69(2):403–6.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Novinec M, Lenarčič B, Baici A. Clusterin is a specific stabilizer and liberator of extracellular cathepsin K. FEBS Lett. 2012;586(7):1062–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Luo X, Suzuki M, Ghandhi SA, Amundson SA, Boothman DA. ATM regulates insulin-like growth factor 1-secretory clusterin (IGF-1-sCLU) expression that protects cells against senescence. PLoS One. 2014;9(6):e99983.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Essabbani A, Garcia L, Zonetti MJ, Fisco T, Pucci S, Chiocchia G. Exon-skipping strategy by ratio modulation between cytoprotective versus pro-apoptotic clusterin forms increased sensitivity of LNCaP to cell death. PLoS One. 2013;8(2):e54920.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bi J, Guo AL, Lai YR, Li B, Zhong JM, Wu HQ, et al. Overexpression of clusterin correlates with tumor progression, metastasis in gastric cancer: a study on tissue microarrays. Neoplasma. 2010;57(3):191–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Zheng W, Sai W, Yao M, Gu H, Yao Y, Qian Q, et al. Silencing clusterin gene transcription on effects of multidrug resistance reversing of human hepatoma HepG2/ADM cells. Tumour Biol. 2015;36(5):3995–4003.CrossRefPubMedGoogle Scholar
  11. 11.
    Bertuzzi M, Marelli C, Bagnati R, Colombi A, Fanelli R, Saieva C, et al. Plasma clusterin as a candidate pre-diagnosis marker of colorectal cancer risk in the Florence cohort of the European Prospective Investigation into Cancer and Nutrition: a pilot study. BMC Cancer. 2015;15:56.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Shabayek MI, Sayed OM, Attaia HA, Awida HA, Abozeed H. Diagnostic evaluation of urinary angiogenin (ANG) and clusterin (CLU) as biomarker for bladder cancer. Pathol Oncol Res. 2014;20(4):859–66.CrossRefPubMedGoogle Scholar
  13. 13.
    Watari H, Kinoshita R, Han Y, Wang L, Hosaka M, Taguchi H, et al. Prognostic significance of clusterin expression in advanced-stage cervical cancer treated with curative intended radiotherapy. Int J Gynecol Cancer. 2012;22(3):465–70.CrossRefPubMedGoogle Scholar
  14. 14.
    Panico F, Casali C, Rossi G, Rizzi F, Morandi U, Bettuzzi S, et al. Prognostic role of clusterin in resected adenocarcinomas of the lung. Lung Cancer. 2013;79(3):294–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Harada K, Miyake H, Kusuda Y, Fujisawa M. Expression of epithelial-mesenchymal transition markers in renal cell carcinoma: impact on prognostic outcomes in patients undergoing radical nephrectomy. BJU Int. 2012;110(11 Pt C):E1131–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Nafee AM, Pasha HF, Abd El Aal SM, Mostafa NA. Clinical significance of serum clusterin as a biomarker for evaluating diagnosis and metastasis potential of viral- related hepatocellular carcinoma. Clin Biochem. 2012;45(13–14):1070–4.CrossRefPubMedGoogle Scholar
  17. 17.
    Kang YK, Hong SW, Lee H, Kim WH. Overexpression of clusterin in human hepatocellular carcinoma. Hum Pathol. 2004;35(11):1340–6.CrossRefPubMedGoogle Scholar
  18. 18.
    M PN. World medical association publishes the revised declaration of Helsinki. Natl Med J India. 2014;27(1):56.Google Scholar
  19. 19.
    O Y. Management of clinical diagnosis, and antiviral therapy for HBV-related cirrhosis. Zhonghua Gan Zang Bing Za Zhi. 2014;22(5):327–335. In Chinese.Google Scholar
  20. 20.
    Ministry of Health of the People’s Republic of China. Updated standards for the diagnosis and treatment of primary liver cancer. Zhonghua Gan Zang Bing Za Zhi. 2012;20(6):419–26. In Chinese.Google Scholar
  21. 21.
    Luo RZ, Cai PQ, Li M, Fu J, Zhang ZY, Chen JW, et al. Decreased expression of PTPN12 correlates with tumor recurrence and poor survival of patients with hepatocellular carcinoma. PLoS One. 2014;9(1):e85592.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yao M, Pan LH, Yao DF. Glypican-3 as a specific biomarker in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2015;14(2):122–3.CrossRefPubMedGoogle Scholar
  23. 23.
    Blumenstein B, Saad F, Hotte S, Chi KN, Eigl B, Gleave M, et al. Reduction in serum clusterin is a potential therapeutic biomarker in patients with castration- resistant prostate cancer treated with custirsen. Cancer Med. 2013;2(4):468–77.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Guo W, Ma X, Xue C, Luo J, Zhu X, Xiang J, et al. Serum clusterin as a tumor marker and prognostic factor for patients with esophageal cancer. Dis Markers. 2014;2014:168960.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Humphries JM, Penno MA, Weiland F, Klingler-Hoffmann M, Zuber A, Boussioutas A, et al. Identification and validation of novel candidate protein biomarkers for the detection of human gastric cancer. Biochim Biophys Acta. 2014;1844(5):1051–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Wang Y, Liu YH, Mai SJ, He LJ, Liao YJ, Deng HX, et al. Evaluation of serum clusterin as a surveillance tool for human hepatocellular carcinoma with hepatitis B virus related cirrhosis. J Gastroenterol Hepatol. 2010;25(6):1123–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Kimura A, Sogawa K, Satoh M, Kodera Y, Yokosuka O, Tomonaga T, et al. The application of a three-step serum proteome analysis for the discovery and identification of novel biomarkers of hepatocellular carcinoma. Int J Proteomics. 2012;2012:623190.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lau SH, Sham JS, Xie D, Tzang CH, Tang D, Ma N, et al. Clusterin plays an important role in hepatocellular carcinoma metastasis. Oncogene. 2006;25(8):1242–50.CrossRefPubMedGoogle Scholar
  29. 29.
    Lai JP, Chen ZM, Lok T, Chan OT, Himmelfarb E, Zhai Q, et al. Immunohistochemical stains of proliferating cell nuclear antigen, insulin-like growth factor 2 and clusterin help distinguish malignant from benign liver nodular lesions. J Clin Pathol. 2014;67(6):464–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Wang C, Jin G, Jin H, Wang N, Luo Q, Zhang Y, et al. Clusterin facilitates metastasis by EIF3I/Akt/MMP13 signaling in hepatocellular carcinoma. Oncotarget. 2015;6(5):2903–16.CrossRefPubMedGoogle Scholar
  31. 31.
    Matsuwaki R, Ishii G, Zenke Y, Neri S, Aokage K, Hishida T, et al. Immuno- phenotypic features of metastatic lymph node tumors to predict recurrence in N2 lung squamous cell carcinoma. Cancer Sci. 2014;105(7):905–11.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Flanagan L, Whyte L, Chatterjee N, Tenniswood M. Effects of clusterin over- expression on metastatic progression and therapy in breast cancer. BMC Cancer. 2010;10(1):107.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Shiota M, Zardan A, Takeuchi A, Kumano M, Beraldi E, Naito S, et al. Clusterin mediates TGF-β-induced epithelial-mesenchymal transition and metastasis via Twist1 in prostate cancer cells. Cancer Res. 2012;72(20):5261–72.CrossRefPubMedGoogle Scholar
  34. 34.
    Wang C, Jiang K, Kang X, Gao D, Sun C, Li Y, et al. Tumor-derived secretory clusterin induces epithelial-mesenchymal transition and facilitates hepatocellular carcinoma metastasis. Int J Biochem Cell Biol. 2012;44(12):2308–20.CrossRefPubMedGoogle Scholar
  35. 35.
    Chen D, Wang Y, Zhang K, Jiao X, Yan B, Liang J. Antisense oligonucleotide against clusterin regulates human hepatocellular carcinoma invasion through transcriptional regulation of matrix metalloproteinase-2 and e-cadherin. Int J Mol Sci. 2012;13(8):10594–607.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Wang X, Luo L, Dong D, Yu Q, Zhao K. Clusterin plays an important role in clear renal cell cancer metastasis. Urol Int. 2014;92(1):95–103.CrossRefPubMedGoogle Scholar
  37. 37.
    Sims JD, McCready J, Jay DG. Extracellular heat shock protein (Hsp) 70 and Hsp90alpha assist in matrix metalloproteinase-2 activation and breast cancer cell migration and invasion. PLoS One. 2011;6(4):e18848.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Wenjie Zheng
    • 1
  • Min Yao
    • 2
  • Wenli Sai
    • 1
  • Qi Qian
    • 3
  • Liuhong Pan
    • 3
  • Liwei Qiu
    • 1
  • Jianfei Huang
    • 4
  • Wei Wu
    • 1
  • Dengfu Yao
    • 1
  1. 1.Research Center of Clinical MedicineAffiliated Hospital of Nantong UniversityNantongChina
  2. 2.Department of ImmunologyMedical School of Nantong UniversityNantongChina
  3. 3.Department of OncologyAffiliated Hospital of Nantong UniversityNantongChina
  4. 4.Department of PathologyAffiliated Hospital of Nantong UniversityNantongChina

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