Skip to main content

Advertisement

SpringerLink
Log in

Recurrence and Poor Prognosis Following Resection of Small Hepatitis B-Related Hepatocellular Carcinoma Lesions Are Associated with Aberrant Tumor Expression Profiles of Glypican 3 and Osteopontin

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Early detection and following appropriate treatments of hepatocellular carcinoma (HCC) is still the gold standard for favored outcome of HCC patients; nevertheless, a small portion of hepatitis B virus (HBV)-related small HCC (<5 cm) patients got poor prognosis. Furthermore, the study for small HBV–HCC was limited. Therefore, the aim of this study was to explore the potential genetic signature for HBV-related small HCC as novel prognostic factors.

Methods

We examined expression profiles of HBV-related small HCC using an Affymetrix U133A GeneChip, evaluated differential gene expression by quantitative real-time polymerase chain reaction (qRT-PCR), and finally validated these expression patterns by immunohistochemistry (IHC).

Results:

A total of 57 genes were differentially expressed between tumor and normal parts (n = 20 pairs) using Affymetrix U133A chip, and 16 genes were further evaluated by qRT-PCR. The result was compatible with the finding of oligonucleotide microarray (Pearson’s correlation, r = 0.87). Furthermore, the expression pattern in HCC tissue by IHC in another group of small HBV–HCC (n = 100) showed overexpression of either osteopontin (OPN) or glypican 3 (GPC3) is an independent prognostic factor for disease-free survival (DFS) in HBV-positive small HCC (P < 0.01 and 0.03, respectively). Long-term DFS and overall survival (OS) for small HBV–HCC patients with high risk (both elevated GPC3+/OPN+) were DFS 0%, OS 0%, respectively; on the other hand, DFS and OS in patients with moderate (only 1 gene elevated) or low (OPN−/GPC3−) risk were 35.0 and 46.5%, respectively.

Conclusions

Elevation of both OPN and GPC3 may act as an adverse indicator for HBV-related small HCC patients after curative resection.

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

Similar content being viewed by others

References

  1. Bosch FX, Ribes J, Diaz M, Cléries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127:S5–16.

    Article  PubMed  Google Scholar 

  2. Department of Health, Taiwan. Health statistics in Taiwan, 2006. http://www.doh.gov.tw/ufile/doc/Chapter%202.pdf.

  3. Chen DS. Hepatocellular carcinoma in Taiwan. Hepatol Res. 2007;37:S101–5.

    Article  PubMed  Google Scholar 

  4. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73.

    Article  PubMed  CAS  Google Scholar 

  5. Lu SN, Su WW, Yang SS, Chang TT, Cheng KS, Wu JC, et al. Secular trends and geographic variations of hepatitis B virus and hepatitis C virus-associated hepatocellular carcinoma in Taiwan. Int J Cancer. 2006;119:1946–52.

    Article  PubMed  CAS  Google Scholar 

  6. Qin LX, Tang ZY. The prognostic significance of clinical and pathological features in hepatocellular carcinoma. World J Gastroenterol. 2002;8:193–9.

    PubMed  Google Scholar 

  7. Lee WC, Jeng LB, Chen MF. Estimation of prognosis after hepatectomy for hepatocellular carcinoma. Br J Surg. 2002;89:311–6.

    Article  PubMed  Google Scholar 

  8. Tung-Ping PR, Fan ST, Wong J. Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg. 2000;232:10–24.

    Article  Google Scholar 

  9. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology. 2002;35:519–24.

    Article  PubMed  Google Scholar 

  10. Yanaga K. Current status of hepatic resection for hepatocellular carcinoma. J Gastroenterol. 2004;39:919–26.

    Article  PubMed  Google Scholar 

  11. Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg. 2002;235:373–82.

    Article  PubMed  Google Scholar 

  12. Zhou Y, Zhao Y, Li B, Xu D, Yin Z, Xie F, et al. Meta-analysis of radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma. BMC Gastroenterol. 2010;10:78.

    Article  PubMed  Google Scholar 

  13. Carr BI, Kanke F, Wise M, Satomura S. Clinical evaluation of lens culinaris agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States. Dig Dis Sci. 2007;52:776–82.

    Article  PubMed  CAS  Google Scholar 

  14. Malaguarnera G, Giordano M, Paladina I, Berretta M, Cappellani A, Malaguarnera M. Serum markers of hepatocellular carcinoma. Dig Dis Sci. 2010;55:2744–55.

    Article  PubMed  CAS  Google Scholar 

  15. Ge X, Yamamoto S, Tsutsumi S, Midorikawa Y, Ihara S, Wang SM, et al. Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics. 2005;86:127–41.

    Article  PubMed  CAS  Google Scholar 

  16. Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA. 1998;95:14863–68.

    Article  PubMed  CAS  Google Scholar 

  17. Lee YS, Chen CH, Tsai CN, Tsai CL, Chao A, Wang TH. Microarray labeling extension values: laboratory signatures for Affymetrix GeneChips. Nucleic Acids Res. 2009;37:1–12.

    Article  Google Scholar 

  18. Ho MC, Lin JJ, Chen CN, Chen CC, Lee H, Yang CY, et al. A gene expression profile for vascular invasion can predict the recurrence after resection of hepatocellular carcinoma: a microarray approach. Ann Surg Oncol. 2006;13:1474–84.

    Article  PubMed  Google Scholar 

  19. Wang SM, Ooi LL, Hui KM. Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma. Clin Cancer Res. 2007;13:6275–83.

    Article  PubMed  CAS  Google Scholar 

  20. Iizuka N, Oka M, Yamada-Okabe H, Nishida M, Maeda Y, Mori N, et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet. 2003;361:923–9.

    Article  PubMed  CAS  Google Scholar 

  21. Yoshioka S, Takemasa I, Nagano H, Kittaka N, Noda T, Wada H, et al. Molecular prediction of early recurrence after resection of hepatocellular carcinoma. Eur J Cancer. 2009;45:881–9.

    Article  PubMed  CAS  Google Scholar 

  22. Moribe T, Iizuka N, Miura T, Kimura N, Tamatsukuri S, Ishitsuka H, et al. Methylation of multiple genes as molecular markers for diagnosis of a small, well-differentiated hepatocellular carcinoma. Int J Cancer. 2009;125:388–97.

    Article  PubMed  CAS  Google Scholar 

  23. Okamoto M, Utsunomiya T, Wakiyama S, Hashimoto M, Fukuzawa K, Ezaki T, et al. Specific gene-expression profiles of noncancerous liver tissue predict the risk for multicentric occurrence of hepatocellular carcinoma in hepatitis C virus-positive patients. Ann Surg Oncol. 2006;13:947–54.

    Article  PubMed  Google Scholar 

  24. Lee CF, Ling ZQ, Zhao T, Lee KR. Distinct expression patterns in hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma. World J Gastroenterol. 2008;14:6072–7.

    Article  PubMed  Google Scholar 

  25. Okabe H, Satoh S, Kato T, Kitahara O, Yanagawa R, Yamaoka Y, et al. Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res. 2001;61:2129–37.

    PubMed  CAS  Google Scholar 

  26. Nam SW, Park JY, Ramasamy A, Shevade S, Islam A, Long PM, et al. Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling. Hepatology. 2005;42:809–18.

    Article  PubMed  CAS  Google Scholar 

  27. Paradis V, Bieche I, Dargere D, Laurendeau I, Laurent C, Bioulac Sage P, et al. Molecular profiling of hepatocellular carcinomas (HCC) using a large-scale real-time RT-PCR approach: determination of a molecular diagnostic index. Am J Pathol. 2003;163:733–41.

    Article  PubMed  CAS  Google Scholar 

  28. Lee S, Kim S. Gene regulations in HBV-related liver cirrhosis closely correlate with disease severity. J Biochem Mol Biol. 2007;40:814–24.

    Article  PubMed  CAS  Google Scholar 

  29. Wurmbach E, Chen YB, Khitrov G, Zhang W, Roayaie S, Schwartz M, et al. Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology. 2007;45:938–47.

    Article  PubMed  CAS  Google Scholar 

  30. Chuma M, Sakamoto M, Yamazaki K, Ohta T, Ohki M, Asaka M, et al. Expression profiling in multistage hepatocarcinogenesis: identification of HSP70 as a molecular marker of early hepatocellular carcinoma. Hepatology. 2003;37:198–207.

    Article  PubMed  CAS  Google Scholar 

  31. Huang CC, Lee TJ, Chang PH, Lee YS, Chuang CC, Jhang YJ, et al. Expression of cathepsin S and its inhibitor stefin A in sinonasal inverted papilloma. Rhinology. 2010;48:352–7.

    PubMed  Google Scholar 

  32. Quackenbush J. Computational analysis of microarray data. Nat Rev Genet. 2001;2:418–27.

    Article  PubMed  CAS  Google Scholar 

  33. Raychaudhuri S, Stuart JM, Altman RB. Principal components analysis to summarize microarray experiments: application to sporulation time series. Pac Symp Biocomput. 2000:455–66.

  34. Smith MW, Yue ZN, Geiss GK, Sadovnikova NY, Carter VS, Boix L, et al. Identification of novel tumor markers in hepatitis C virus-associated hepatocellular carcinoma. Cancer Res. 2003;63:859–64.

    PubMed  CAS  Google Scholar 

  35. Ishii H, Yamamoto J, Ikari T. Adjuvant treatments for resectable hepatocellular carcinoma. J Hepatobiliary Pancreat Surg. 2008;15:459–62.

    Article  PubMed  Google Scholar 

  36. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.

    Article  PubMed  CAS  Google Scholar 

  37. Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer. 2007;7:599–612.

    Article  PubMed  CAS  Google Scholar 

  38. Liu SP, Li YS, Lee CM, Yen CH, Liao YJ, Huang SF, et al. Higher susceptibility to aflatoxin B(1)-related hepatocellular carcinoma in glycine N-methyltransferase knockout mice. Int J Cancer. 2011;128:511–23.

    Article  PubMed  CAS  Google Scholar 

  39. Ho JC, Cheung ST, Leung KL, Ng IO, Fan ST. Decreased expression of cytochrome P450 2E1 is associated with poor prognosis of hepatocellular carcinoma. Int J Cancer. 2004;111:494–500.

    Article  PubMed  CAS  Google Scholar 

  40. Nakatsura T, Yoshitake Y, Senju S, Monji M, Komori H, Motomura Y, et al. Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker. Biochem Biophys Res Commun. 2003;306:16–25.

    Article  PubMed  CAS  Google Scholar 

  41. Sakamoto M. Early HCC: diagnosis and molecular markers. J Gastroenterol. 2009;44:108–11.

    Article  PubMed  CAS  Google Scholar 

  42. Liu H, Li P, Zhai Y, Qu CF, Zhang LJ, Tan YF, et al. Diagnostic value of glypican-3 in serum and liver for primary hepatocellular carcinoma. World J Gastroenterol. 2010;16:4410–5.

    Article  PubMed  CAS  Google Scholar 

  43. Yang GH, Fan J, Xu Y, Qiu SJ, Yang XR, et al. Osteopontin combined with CD44, a novel prognostic biomarker for patients with hepatocellular carcinoma undergoing curative resection. Oncologist. 2008;13:1155–65.

    Article  PubMed  CAS  Google Scholar 

  44. Korita PV, Wakai T, Shirai Y, Matsuda Y, Sakata J, Cui X, et al. Overexpression of osteopontin independently correlates with vascular invasion and poor prognosis in patients with hepatocellular carcinoma. Hum Pathol. 2008;39:1777–83.

    Article  PubMed  CAS  Google Scholar 

  45. Chen RX, Xia YH, Cui JF, Xue TC, Ye SL. Osteopontin, a single marker for predicting the prognosis of patients with tumor-node-metastasis stage I hepatocellular carcinoma after surgical resection. J Gastroenterol Hepatol. 2010;25:1435–42.

    Article  PubMed  CAS  Google Scholar 

  46. Takafuji V, Forgues M, Unsworth E, Goldsmith P, Wang XW. An osteopontin fragment is essential for tumor cell invasion in hepatocellular carcinoma. Oncogene. 2007;26:6361–71.

    Article  PubMed  CAS  Google Scholar 

  47. Ue T, Yokozaki H, Kitadai Y, Yamamoto S, Yasui W, Ishikawa T, et al. Co-expression of osteopontin and CD44v9 in gastric cancer. Int J Cancer. 1998;79:127–32.

    Article  PubMed  CAS  Google Scholar 

  48. Kim SH, Chung YH, Yang SH, Kim JA, Jang MK, Kim SE, et al. Prognostic value of serum osteopontin in hepatocellular carcinoma patients treated with transarterial chemoembolization. Korean J Hepatol. 2009;15:320–30.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

We are grateful to all our colleagues in the Department of Cancer Center, Pathology and the Genomic Medicine Research Core Laboratory of Chang Gung Memorial Hospital for their technical assistance. This study was supported by Chang Gung Memorial Hospital (CMRPG361521-2, Chen MF; CMRPG391001, Yu MC) and the National Science Council (NMRPG380081, Yu MC), Taiwan.

Author information

Authors and Affiliations

  1. Department of Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

    Ming-Chin Yu MD, Wei-Chen Lee MD & Miin-Fu Chen MD

  2. Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan

    Ming-Chin Yu MD, Hsiang-Yao Wu MS & Chi-Neu Tsai PhD

  3. Department of Biotechnology, Ming Chuan University, Taoyuan, Taiwan

    Yun-Shien Lee PhD

  4. Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Yun-Shien Lee PhD

  5. Department of Pathology, Taipei Medical University Hospital, Taipei, Taiwan

    Sey-En Lin MD, PhD

  6. Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan

    Tse-Ching Chen MD, PhD

Authors
  1. Ming-Chin Yu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun-Shien Lee PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sey-En Lin MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hsiang-Yao Wu MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tse-Ching Chen MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei-Chen Lee MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Miin-Fu Chen MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chi-Neu Tsai PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Miin-Fu Chen MD or Chi-Neu Tsai PhD.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 52 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yu, MC., Lee, YS., Lin, SE. et al. Recurrence and Poor Prognosis Following Resection of Small Hepatitis B-Related Hepatocellular Carcinoma Lesions Are Associated with Aberrant Tumor Expression Profiles of Glypican 3 and Osteopontin. Ann Surg Oncol 19 (Suppl 3), 455–463 (2012). https://doi.org/10.1245/s10434-011-1946-2

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-011-1946-2

Keywords

Search

Navigation