Skip to main content

Advertisement

SpringerLink
Log in

Expression of Hepatocyte Growth Factor Activator Inhibitor Type 1 in Human Hepatocellular Carcinoma and Postoperative Outcomes

  • Published:
World Journal of Surgery Aims and scope Submit manuscript

Abstract

Background

Hepatocyte growth factor activator inhibitor type 1 (HAI-1), one of the Kunitz-type serine protease inhibitors, has an important role in cancer progression through regulation of the activity of hepatocyte growth factor. HAI-1 is expressed in hepatocellular carcinoma (HCC) to various degrees. Investigation of the relationship between HAI-1 expression and clinicopathological features of HCC may contribute to improved treatment outcomes for HCC through understanding the mechanism of tumor progression or improvement in the prediction of tumor malignancy.

Methods

The study included 121 HCC patients treated surgically from 1996 to 2005. We performed immunohistological examination for HAI-1 in resected HCC specimens by use of anti-human HAI-1 monoclonal antibody. Clinicopathological features, including postoperative overall survival (OS) and disease-free survival (DFS) rates, were compared between the immunoreaction positive and negative groups.

Results

The immunoreaction positive group included 38 patients (31%), and the negative group included 83 patients (69%). OS and DFS rates were significantly higher in the HAI-1 negative group than in the positive group. HAI-1 positivity related to multiplicity, vascular invasion, and characteristics of advanced tumor stage. In multivariate analysis, expression of HAI-1 was a significant independent prognostic tumor factor.

Conclusions

Expression of HAI-1 in HCC cells is associated with poor prognosis for HCC patients. HAI-1 may be important in HCC progression and may be a new prognostic factor for HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. World Health Organization. Mortality database. Available at http://www.who.int/whosis/en. Accessed Feb 2009

  2. Liver Cancer Study Group of Japan (1990) Primary liver cancer in Japan. Clinicopathologic features and results of surgical treatment. Ann Surg 211:277–287

    Google Scholar 

  3. Carr BI (2004) Hepatocellular carcinoma: current management and future trends. Gastroenterology 127:S218–S224

    Article  PubMed  Google Scholar 

  4. Shirabe K, Takenaka K, Taketomi A et al (1996) Postoperative hepatitis status as a significant risk factor for recurrence in cirrhotic patients with small hepatocellular carcinoma. Cancer 77:1050–1055

    Article  CAS  PubMed  Google Scholar 

  5. Aramaki M, Kawano K, Kai T et al (1999) Treatment for extrahepatic metastasis of hepatocellular carcinoma following successful hepatic resection. Hepatogastroenterology 46:2931–2934

    CAS  PubMed  Google Scholar 

  6. Kuang M, Peng BG, Lu MD et al (2004) Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin Cancer Res 10:1574–1579

    Article  CAS  PubMed  Google Scholar 

  7. Lau WY, Leung TW, Ho SK et al (1999) Adjuvant intra-arterial iodine-131-labelled lipiodol for respectable hepatocellular carcinoma: a prospective randomized trial. Lancet 353:797–801

    Article  CAS  PubMed  Google Scholar 

  8. Jeffers M, Rong S, Van de Woude GF (1996) Enhanced tumorigenicity and invasion-metastasis by hepatocyte growth factor/scatter factor-met signalling in human cells concomitant with induction of the urokinase proteolysis network. Mol Cell Biol 16:1115–1125

    CAS  PubMed  Google Scholar 

  9. Kamiyama T, Une Y, Uchino J et al (1998) Hepatocyte growth factor enhances the invasion activity of human hepatocellular carcinoma cell lines. Int J Oncol 12:655–659

    CAS  PubMed  Google Scholar 

  10. Monvoisin A, Neaud V, De Lédinghen V et al (1999) Direct evidence that hepatocyte growth factor-induced invasion of hepatocellular carcinoma cells is mediated by urokinase. J Hepatol 30:511–518

    Article  CAS  PubMed  Google Scholar 

  11. Santoni-Rugiu E, Preisegger KH, Kiss A et al (1996) Inhibition of neoplastic development in the liver by hepatocyte growth factor in a transgenic mouse model. Proc Natl Acad Sci USA 93:9577–9582

    Article  CAS  PubMed  Google Scholar 

  12. Liu ML, Mars WM, Michalopoulos GK (1995) Hepatocyte growth factor inhibits cell proliferation in vivo of rat hepatocellular carcinomas induced by dimethylnitrosamine. Carcinogenesis 16:841–843

    Article  CAS  PubMed  Google Scholar 

  13. Suzuki K, Hayashi N, Yamada Y et al (1994) Expression of the c-met protooncogene in human hepatocellular carcinoma. Hepatology 20:1231–1236

    Article  CAS  PubMed  Google Scholar 

  14. D’Errico A, Fiorentino M, Ponzetto A et al (1996) Liver hepatocyte growth factor does not always correlate with hepatocellular proliferation in human liver lesions: its specific receptor c-met does. Hepatology 24:60–64

    PubMed  Google Scholar 

  15. Ueki T, Fujimoto J, Suzuki T et al (1997) Expression of hepatocyte growth factor and its receptor c-met proto-oncogene in hepatocellular carcinoma. Hepatology 25:862–866

    Article  CAS  PubMed  Google Scholar 

  16. Shimomura T, Ochiai M, Kondo J et al (1992) A novel protease obtained from FBS-containing culture supernatant, that processes single-chain form hepatocyte growth factor to two chain form in serum-free culture. Cytotechnology 8:219–229

    Article  CAS  PubMed  Google Scholar 

  17. Shimomura T, Kondo J, Ochiai M et al (1993) Activation of the zymogen of hepatocyte growth factor activator by thrombin. J Biol Chem 268:22927–22932

    CAS  PubMed  Google Scholar 

  18. Shimomura T, Denda K, Kitamura A et al (1997) Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitor. J Biol Chem 272:6370–6376

    Article  CAS  PubMed  Google Scholar 

  19. Nagata K, Hirono S, Ido A et al (2001) Expression of hepatocyte growth factor activator and hepatocyte growth factor activator inhibitor type 1 in human hepatocellular carcinoma. Biochem Biophys Res Commun 289:205–211

    Article  CAS  PubMed  Google Scholar 

  20. Kondo K, Chijiiwa K, Funagayama M et al (2008) Hepatic resection is justified for elderly patients with hepatocellular carcinoma. World J Surg 32:2223–2229

    Article  PubMed  Google Scholar 

  21. Fujiyama S, Morishita T, Hashiguchi O et al (1988) Plasma abnormal prothrombin (des-gamma-carboxy prothrombin) as a marker of hepatocellular carcinoma. Cancer 61:1621–1628

    Article  CAS  PubMed  Google Scholar 

  22. Kataoka H, Suganuma T, Shimomura T et al (1999) Distribution of hepatocyte growth factor activator inhibitor type 1 (HAI-1) in human tissues: cellular surface localization of HAI-1 in simple columnar epithelium and its modulated expression in injured and regenerative tissues. J Histochem Cytochem 47:673–682

    CAS  PubMed  Google Scholar 

  23. Pugh RN, Murray-Lyon IM, Dawson JL et al (1973) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60:646–649

    Article  CAS  PubMed  Google Scholar 

  24. Liver Cancer Study Group of Japan (2003) General rules for the clinical and pathological study of primary liver cancer, 2nd edn. Kanehara Press, Tokyo

    Google Scholar 

  25. Poon RTP, Fan ST, Wong J (2000) Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg 232:10–24

    Article  Google Scholar 

  26. Kondo K, Chijiiwa K, Makino I et al (2005) Risk factors for early death after liver resection in patients with solitary hepatocellular carcinoma. J Hepatobiliary Pancreat Surg 12:399–404

    Article  PubMed  Google Scholar 

  27. Ke AW, Shi GM, Zhou J et al (2009) Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology 49:491–503

    Article  CAS  PubMed  Google Scholar 

  28. Kataoka H, Miyata S, Uchinokura S et al (2003) Roles of hepatocyte growth factor (HGF) activator and HGF activator inhibitor in the pericellular activation of HGF/scatter factor. Cancer Metastasis Rev 22:223–236

    Article  CAS  PubMed  Google Scholar 

  29. Tsai WC, Chao YC, Lee WH et al (2006) Increasing EMMPRIN and matriptase expression in hepatocellular carcinoma: tissue microarray analysis of immunohistochemical scores with clinicopathological parameters. Histopathology 49:388–395

    Article  PubMed  Google Scholar 

  30. Kang JY, Dolled-Filhart M, Ocal IT et al (2003) Tissue microarray analysis of hepatocyte growth factor/Met pathway components reveals a role for Met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer. Cancer Res 63:1101–1105

    CAS  PubMed  Google Scholar 

  31. Knudsen BS, Lucas JM, Fazli L et al (2005) Regulation of hepatocyte activator inhibitor-1 expression by androgen and oncogenic transformation in the prostate. Am J Pathol 167:255–266

    CAS  PubMed  Google Scholar 

  32. Miyata S, Uchinokura S, Fukushima T et al (2005) Diverse roles of hepatocyte growth factor activator inhibitor type 1 (HAI-1) in the growth of glioblastoma cells in vivo. Cancer Lett 227:83–93

    Article  CAS  PubMed  Google Scholar 

  33. Kataoka H, Shimomura T, Kawaguchi T et al (2000) Hepatocyte growth factor activator inhibitor type 1 is a specific cell surface binding protein of hepatocyte growth factor activator (HGFA) and regulates HGFA activity in the pericellular microenvironment. J Biol Chem 275:40453–40462

    Article  CAS  PubMed  Google Scholar 

  34. Itoh H, Naganuma S, Takeda N et al (2004) Regeneration of injured intestinal mucosa is impaired in hepatocyte growth factor activator-deficient mice. Gastroenterology 127:1423–1435

    Article  CAS  PubMed  Google Scholar 

  35. Itoh H, Kataoka H (2002) Roles of hepatocyte growth factor activator (HGFA) and its inhibitor HAI-1 in the regeneration of injured gastrointestinal mucosa. J Gastroenterol 37(Suppl 14):15–21

    PubMed  Google Scholar 

  36. Oberst MD, Chen LY, Kiyomiya K et al (2005) HAI-1 regulates activation and expression of matriptase, a membrane-bound serine protease. Am J Physiol Cell Physiol 289:C462–C470

    Article  CAS  PubMed  Google Scholar 

  37. Kirchhofer D, Peek M, Lipari MT et al (2005) Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-1B (HAI-1B) and HAI-2. FEBS Lett 579:1945–1950

    Article  CAS  PubMed  Google Scholar 

  38. Chen CH, Su KY, Tao MH et al (2006) Decreased expressions of hepsin in human hepatocellular carcinomas. Liver Int 26:774–780

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

A part of this study was supported by Grants-in-Aid (Nos. 17591417, No 20591635, and 20390114) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Author information

Authors and Affiliations

  1. Department of Surgical Oncology and Regulation of Organ Function, Miyazaki University School of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan

    Mayumi Funagayama, Kazuhiro Kondo & Kazuo Chijiiwa

  2. Section of Oncology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan

    Hiroaki Kataoka

Authors
  1. Mayumi Funagayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuhiro Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazuo Chijiiwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroaki Kataoka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kazuo Chijiiwa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Funagayama, M., Kondo, K., Chijiiwa, K. et al. Expression of Hepatocyte Growth Factor Activator Inhibitor Type 1 in Human Hepatocellular Carcinoma and Postoperative Outcomes. World J Surg 34, 1563–1571 (2010). https://doi.org/10.1007/s00268-010-0517-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00268-010-0517-1

Keywords

Search

Navigation