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High ADAM8 Expression is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma

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Pathology & Oncology Research

Abstract

In this study,we investigated the ADAM8 expression in hepatocellular carcinoma (HCC) and its correlation with clinicopathologic features,including the survival of patients with HCC. Furthermore,we examined the biological processes regulated by ADAM8 during the development of using HepG2 cell line as a model system. We used immunohistochemistry to compare ADAM8 protein expression in HCC and normal liver tissues and further analyze the ADAM8 protein expression in clinicopathologically characterized 105 HCC cases.We stably knocked down the endogenous expression level of ADAM8 in HepG2 cells with specific shRNA-expressing lentiviral vector. Following the successful establishment of stable cells,we examined in vitro cell growth by MTT assay,anchorage-independent growth by soft-agar colony formation assay and cell migration/invasion by transwell and boyden chamber assay. And in addition,we also investigated the in vivo tumor growth by xenograft transplantation of HepG2 cells into nude mice. Protein expression level of ADAM8 was markedly higher in HCC tissues than that in the normal liver tissues (P = 0.0058).In addition,high expression of ADAM8 protein was positively correlated with serum AFP elevation,tumor size,histological differentiation,tumor recurrence,tumor metastasis,and tumor stage. Patients with higher ADAM8 expression showed a significantly shorter overall survival time than patients with low ADAM8 expression. Multivariate analysis suggested that ADAM8 expression might be an independent prognostic indicator (p = 0.016) for the survival of patients with HCC. ADAM8-specific shRNA (shADAM8) successfully knocked down its endogenous expression in HepG2 cells. Compared to the parental and control shRNA-transfected (shCtrl) HepG2 cells,the shADAM8 cells exhibited significantly reduced in vitro cell growth,anchorage-independent growth,cell migration and invasion (p < 0.05).In vivo,the xenograft transplants from shADAM8 cells gave rise to much smaller tumors as compared to those from shCtrl cells. High ADAM8 expression is associated with poor overall survival in patients with HCC. Down-regulation of ADAM8 inhibits the growth,anchorage-independent growth,migration and invasion of HepG2 cells. ADAM8 may be a potential target of antiangiogenic therapy for HCC.

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References

  1. Shariff MI, Cox IJ, Gomaa AI, Khan SA, Gedroyc W, TaylorRobinson SD (2009) Hepatocellular carcinoma:current trends in worldwide epidemiology, risk factors, diagnosis and therapeutics. Expert Rev Gastroenterol Hepatol 3:353–367

    Article  PubMed  Google Scholar 

  2. Lau WY, Lai EC (2008) Hepatocellular carcinoma:current management and recent advances. Hepatobiliary Pancreat Dis Int 7:237–257

    PubMed  Google Scholar 

  3. Koorey D (2007) Hepatocellular carcinoma:prevention, detection and treatment in the real world. Intern Med J 37:513–515

    Article  PubMed  CAS  Google Scholar 

  4. Pleguezuelo M, Marelli L, Misseri M, Germani G, Calvaruso V, Xiruochakis E et al (2008) TACE versus TAE as therapy for hepatocellular carcinoma. Expert Rev Anticancer Ther 8:1623–1641

    Article  PubMed  CAS  Google Scholar 

  5. Yoshiyama K, Higuchi Y, Kataoka M, Matsuura K, Yamamoto S (1997) CD156(human ADAM8):expression, primary amino acid sequence, and gene location. Genomics 41(1):56–62

    Article  PubMed  CAS  Google Scholar 

  6. Yamamoto S, Higuchi Y, Yoshiyama K et al (1999) ADAM family proteins in the immune system. Immunol Today 20(6):278–284

    Article  PubMed  CAS  Google Scholar 

  7. Schlomann U, Wildeboer D, Webster A et al (2002) The metalloprotease disintegrin ADAM8. Processing by autocatalysis is required for proteolytic activity and cell adhesion. Biol Chem 277(50):48210–48219

    Article  CAS  Google Scholar 

  8. Primakoff P, Myles DG (2000) The ADAM gene family:surface proteins with adhesion and protease activity. Trends Genet 16(2):83–87

    Article  PubMed  CAS  Google Scholar 

  9. Seals DF, Courtneidge SA (2003) The ADAMs family of metalloproteases:multidomain proteins with multiple functions. Genes Dev 17(1):7–30

    Article  PubMed  CAS  Google Scholar 

  10. Fourie AM, Coles F, Moreno V, Karlsson L (2003) Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on synthetic peptide substrates and in ectodomain cleavage of CD23. J Biol Chem 278(33):30469–30477

    Article  PubMed  CAS  Google Scholar 

  11. Naus S, Richter M, Wildeboer D, Moss M, Schachner M, Bartsch JW (2004) Ectodomain shedding of the neural recognition molecule CHL1 by the metalloprotease-disintegrin ADAM8 promotes neurite outgrowth and suppresses neuronal cell death. J Biol Chem 279(16):16083–16090

    Article  PubMed  CAS  Google Scholar 

  12. Karan D, Lin FC, Bryan M et al (2003) Expression of ADAMs (a disintegrin and metalloproteases) and TIMP-3 (tissue inhibitor of metalloproteinase-3) in human prostatic adenocarcinomas. Int J Oncol 23(5):1365–1371

    PubMed  CAS  Google Scholar 

  13. O’Shea C, McKie N, Buggy Y et al (2003) Expression of ADAM-9 mRNA and protein in human breast cancer. Int J Cancer 105(6):754–761

    Article  PubMed  Google Scholar 

  14. Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ et al (2008) High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol 26:2707–2716

    Article  PubMed  Google Scholar 

  15. Valkovskaya N, Kayed H, Felix K, Hartmann D, Giese NA, Osinsky SP, Friess H, Kleeff J (2007) ADAM8 expression is associated with increased invasiveness and reduced patient survival in pancreatic cancer. J Cell Mol Med 11(5):1162–1174

    Article  PubMed  CAS  Google Scholar 

  16. Valkovskaya NV (2008) Hypoxia-dependent expression of ADAM8 in human pancreatic cancer cell lines. Exp Oncol 30(2):129–132

    PubMed  CAS  Google Scholar 

  17. Kelly K, Crowley J, Bunn PA Jr et al (2001) Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer:a Southwest Oncology Group trial. J Clin Oncol 19(13):3210–3218

    PubMed  CAS  Google Scholar 

  18. Hennessy BT, Hanrahan EO, Daly PA (2004) Non-Hodgkin lymphoma:an update. Lancet Oncol 5(6):341–353

    Article  PubMed  Google Scholar 

  19. Pujol JL, Grenier J, Daures JP, Daver A, Pujol H, Michel FB (1993) Serum fragment of cytokeratin subunit 19 measured by CYFRA 21–1 immunoradiometric assay as a marker of lung cancer. Cancer Res 53(1):61–66

    PubMed  CAS  Google Scholar 

  20. Miyake Y, Kodama T, Yamaguchi K (1994) Pro-gastrin-releasing peptide(31–98) is a specific tumor marker in patients with small cell lung carcinoma. Cancer Res 54(8):2136–2140

    PubMed  CAS  Google Scholar 

  21. Michael M, Babic B, Khokha R et al (1999) Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer. J Clin Oncol 17(6):1802–1808

    PubMed  CAS  Google Scholar 

  22. Peng SY, Lai PL, Chu JS et al (1993) Expression and hypomethylation of alpha-fetoprotein gene in unicentric and multicentric human hepatocellular carcinomas. Hepatology 17:35–41

    Article  PubMed  CAS  Google Scholar 

  23. Hsu HC, Jeng YM, Mao TL, Chu JS, Lai PL, Peng SY (2000) b-Catenin mutations are associated with a subset of low stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am J Pathol 157:763–770

    Article  PubMed  CAS  Google Scholar 

  24. Tuck AB, O'Malley FP, Singhal H et al (1998) Osteopontin expression in a group of lymph node negative breast cancer patients. Int J Cancer 79:502–508

    Article  PubMed  CAS  Google Scholar 

  25. Ue T, Yokozaki H, Kitadai Y et al (1998) Co-expression of osteopontin and CD44v9 in gastric cancer. Int J Cancer 79:127–132

    Article  PubMed  CAS  Google Scholar 

  26. Hwang YH, Choi JY, Kim S et al (2004) Over-expression of c-raf-1proto-oncogene in liver cirrhosis and hepatocellular carcinoma. Hepatol Res 29(2):113–121

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of General Surgery, Yixing People’s Hospital, No. 75, Tongzhen Guan Rd., Yixing, 214200, China

    Yun Zhang, Yong-Fei Tan, Chao Jiang, Kai Zhang, Tian-Zhou Zha & Miao Zhang

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  1. Yun Zhang
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  2. Yong-Fei Tan
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  3. Chao Jiang
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  4. Kai Zhang
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  5. Tian-Zhou Zha
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  6. Miao Zhang
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Correspondence to Yong-Fei Tan.

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Zhang, Y., Tan, YF., Jiang, C. et al. High ADAM8 Expression is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma. Pathol. Oncol. Res. 19, 79–88 (2013). https://doi.org/10.1007/s12253-012-9560-6

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  • DOI: https://doi.org/10.1007/s12253-012-9560-6

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