Skip to main content

Advertisement

SpringerLink
Log in

MET is a predictive factor for late recurrence but not for overall survival of early stage hepatocellular carcinoma

  • Research Article
  • Published:
Tumor Biology

Abstract

The MET and RON receptors are tyrosine kinases that form a non-covalent complex on the cell surface that functions in several steps of tumor progression. The purpose of this study was to determine the clinical significance of MET and RON expression on long-term survival and recurrence after curative resection in a large cohort of hepatocellular carcinoma (HCC) patients. We performed immunohistochemical analyses on microarrays of the tumors using antibodies against MET and RON. We evaluated the prognostic value of biomarker expression using Cox regression and the Kaplan–Meier method in 490 HCC patients. MET-positive patients had higher overall recurrence rates than MET-negative patients (P = 0.041); however, MET positivity was not associated with overall survival (OS) (P = 0.249). RON was not associated with overall recurrence rates and OS. MET was independently associated with late but not early phase recurrence. Particularly, the prognostic significance of MET is limited in early stage disease. MET+/RON+ patients had higher overall recurrence rates than those with the other expression patterns (P = 0.071), although the result did not reach statistical significance. Immunohistological activation of MET expression has no prognostic significance for OS in patients with HCC. However, MET positivity was correlated with late recurrence after HCC resection in early stage disease.

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

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

    Article  PubMed  Google Scholar 

  2. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005;25:181–200.

    Article  PubMed  Google Scholar 

  3. Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, et al. Predicting hepatitis b virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003;9:416–23.

    Article  CAS  PubMed  Google Scholar 

  4. Siegel AB, Olsen SK, Magun A, Brown RS. Sorafenib: where do we go from here? Hepatology. 2010;52:360–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mann CD, Neal CP, Garcea G, Manson MM, Dennison AR, Berry DP. Prognostic molecular markers in hepatocellular carcinoma: a systematic review. Eur J Cancer. 2007;43:979–92.

    Article  CAS  PubMed  Google Scholar 

  6. Zarnegar R, DeFrances MC, Kost DP, Lindroos P, Michalopoulos GK. Expression of hepatocyte growth factor mRNA in regenerating rat liver after partial hepatectomy. Biochem Biophys Res Commun. 1991;177:559–65.

    Article  CAS  PubMed  Google Scholar 

  7. Benvenuti S, Comoglio PM. The MET receptor tyrosine kinase in invasion and metastasis. J Cell Physiol. 2007;213:316–25.

    Article  CAS  PubMed  Google Scholar 

  8. Comoglio PM, Giordano S, Trusolino L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov. 2008;7:504–16.

    Article  CAS  PubMed  Google Scholar 

  9. Masuya D, Huang C, Liu D, Nakashima T, Kameyama K, Haba R, et al. The tumour-stromal interaction between intratumoral c-MET and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer patients. Br J Cancer. 2004;90:1555–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Aune G, Lian AM, Tingulstad S, Torp SH, Forsmo S, Reseland JE, et al. Increased circulating hepatocyte growth factor (HGF): a marker of epithelial ovarian cancer and an indicator of poor prognosis. Gynecol Oncol. 2011;121:402–6.

    Article  CAS  PubMed  Google Scholar 

  11. Koh Y, Park C, Hyun Yoon D, Suh C, Huh J. MET and MST1R as prognostic factors for classical Hodgkin’s lymphoma. Mod Pathol: an official journal of the United States and Canadian Academy of Pathology, Inc. 2013;26:1172–82.

    Article  CAS  Google Scholar 

  12. Kondo S, Ojima H, Tsuda H, Hashimoto J, Morizane C, Ikeda M, Ueno H, Tamura K, Shimada K, Kanai Y, Okusaka T: Clinical impact of c-Met expression and its gene amplification in hepatocellular carcinoma. Int J Clin Oncol. 2012.

  13. Chu JS, Ge FJ, Zhang B, Wang Y, Silvestris N, Liu LJ, et al. Expression and prognostic value of VEGFR-2, PDGFR-β, and c-Met in advanced hepatocellular carcinoma. J Exp Clin Cancer Res. 2013;32:16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee SJ, Lee J, Sohn I, Mao M, Kai W, Park CK, et al. A survey of c-Met expression and amplification in 287 patients with hepatocellular carcinoma. Anticancer Res. 2013;33:5179–86.

    CAS  PubMed  Google Scholar 

  15. Wang MH, Wang D, Chen YQ. Oncogenic and invasive potentials of human macrophage-stimulating protein receptor, the RON receptor tyrosine kinase. Carcinogenesis. 2003;24:1291–300.

    Article  CAS  PubMed  Google Scholar 

  16. Bardella C, Costa B, Maggiora P, Patane’ S, Olivero M, Ranzani GN, et al. Truncated RON tyrosine kinase drives tumor cell progression and abrogates cell-cell adhesion through e-cadherin transcriptional repression. Cancer Res. 2004;64:5154–61.

    Article  CAS  PubMed  Google Scholar 

  17. Wang MH, Kurtz AL, Chen Y. Identification of a novel splicing product of the ron receptor tyrosine kinase in human colorectal carcinoma cells. Carcinogenesis. 2000;21:1507–12.

    Article  CAS  PubMed  Google Scholar 

  18. Hui MK, Lai KK, Chan KW, Luk JM, Lee NP, Chung Y, Cheung LC, Srivastava G, Tsao SW, Tang JC, Law S: Prognostic significance of phosphorylated RON in esophageal squamous cell carcinoma. Med Oncol. 2011.

  19. Catenacci DV, Cervantes G, Yala S, Nelson EA, El-Hashani E, Kanteti R, et al. Ron (mst1r) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma. Cancer Biol Ther. 2011;12:9–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee CT, Chow NH, Su PF, Lin SC, Lin PC, Lee JC. The prognostic significance of RON and MET receptor coexpression in patients with colorectal cancer. Dis Colon Rectum. 2008;51:1268–74.

    Article  PubMed  Google Scholar 

  21. Lee WY, Chen HH, Chow NH, Su WC, Lin PW, Guo HR. Prognostic significance of co-expression of RON and MET receptors in node-negative breast cancer patients. Clin Cancer Res. 2005;11:2222–8.

    Article  CAS  PubMed  Google Scholar 

  22. Cheng HL, Liu HS, Lin YJ, Chen HH, Hsu PY, Chang TY, et al. Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder. Br J Cancer. 2005;92:1906–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. EDMONDSON HA, STEINER PE. Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer. 1954;7:462–503.

    Article  CAS  PubMed  Google Scholar 

  24. Portolani N, Coniglio A, Ghidoni S, Giovanelli M, Benetti A, Tiberio GA, et al. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg. 2006;243:229–35.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Chen Q, Seol DW, Carr B, Zarnegar R. Co-expression and regulation of MET and RON proto-oncogenes in human hepatocellular carcinoma tissues and cell lines. Hepatology. 1997;26:59–66.

    CAS  PubMed  Google Scholar 

  26. Sohn W, Paik YH, Kim JM, Kwon CH, Joh JW, Cho JY, et al. HBV DNA and BHsAG levels as risk predictors of early and late recurrence after curative resection of HBV-related hepatocellular carcinoma. Ann Surg Oncol. 2014;21:2429–35.

    Article  PubMed  Google Scholar 

  27. Du ZG, Wei YG, Chen KF, Li B. Risk factors associated with early and late recurrence after curative resection of hepatocellular carcinoma: a single institution’s experience with 398 consecutive patients. Hepatobiliary Pancreat Dis Int. 2014;13:153–61.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang W, Song TQ, Zhang T, Wu Q, Kong DL, Li Q, et al. Adjuvant interferon for early or late recurrence of hepatocellular carcinoma and mortality from hepatocellular carcinoma following curative treatment: a meta-analysis with comparison of different types of hepatitis. Mol Clin Oncol. 2014;2:1125–34.

    PubMed  PubMed Central  Google Scholar 

  29. Di Renzo MF, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L, et al. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res. 1995;1:147–54.

    PubMed  Google Scholar 

  30. Di Renzo MF, Olivero M, Martone T, Maffe A, Maggiora P, Stefani AD, et al. Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene. 2000;19:1547–55.

    Article  PubMed  Google Scholar 

  31. Peace BE, Hughes MJ, Degen SJ, Waltz SE. Point mutations and overexpression of RON induce transformation, tumor formation, and metastasis. Oncogene. 2001;20:6142–51.

    Article  CAS  PubMed  Google Scholar 

  32. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4:915–25.

    Article  CAS  PubMed  Google Scholar 

  33. Danilkovitch A, Donley S, Skeel A, Leonard EJ. Two independent signaling pathways mediate the antiapoptotic action of macrophage-stimulating protein on epithelial cells. Mol Cell Biol. 2000;20:2218–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ma PC, Kijima T, Maulik G, Fox EA, Sattler M, Griffin JD, et al. C-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res. 2003;63:6272–81.

    CAS  PubMed  Google Scholar 

  35. Ma PC, Tretiakova MS, MacKinnon AC, Ramnath N, Johnson C, Dietrich S, et al. Expression and mutational analysis of MET in human solid cancers. Genes Chromosom Cancer. 2008;47:1025–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jagadeeswaran R, Ma PC, Seiwert TY, Jagadeeswaran S, Zumba O, Nallasura V, et al. Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma. Cancer Res. 2006;66:352–61.

    Article  CAS  PubMed  Google Scholar 

  37. Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997;16:68–73.

    Article  CAS  PubMed  Google Scholar 

  38. Park WS, Dong SM, Kim SY, Na EY, Shin MS. Somatic mutations in the kinase domain of the MET/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res. 1999;59:307–10.

    CAS  PubMed  Google Scholar 

  39. Follenzi A, Bakovic S, Gual P, Stella MC, Longati P, Comoglio PM. Cross-talk between the proto-oncogenes MET and RON. Oncogene. 2000;19:3041–9.

    Article  CAS  PubMed  Google Scholar 

  40. O’Toole JM, Rabenau KE, Burns K, Lu D, Mangalampalli V, Balderes P, et al. Therapeutic implications of a human neutralizing antibody to the macrophage-stimulating protein receptor tyrosine kinase (RON), a c-MET family member. Cancer Res. 2006;66:9162–70.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Pathology, Ajou University School of Medicine, Suwon, Republic of Korea

    Young Wha Koh

  2. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Seoul, 138-736, Republic of Korea

    Yang-Soon Park, Hyo Jeong Kang & Eunsil Yu

  3. Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Ju Hyun Shim

Authors
  1. Young Wha Koh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yang-Soon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hyo Jeong Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ju Hyun Shim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eunsil Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eunsil Yu.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig. 1

MET and RON expression in normal hepatic tissue and hepatocellular carcinoma (HCC) tissue. Normal hepatic tissue cells show no reactivity for MET (A) and RON (B). HCC cells show strong MET (C) and RON (D) immunostaining on the cell membrane and cytoplasm. (JPEG 1,039 kb)

(JPEG 988 kb)

(JPEG 821 kb)

(JPEG 884 kb)

Supplementary Table 1

(DOC 71 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koh, Y.W., Park, YS., Kang, H.J. et al. MET is a predictive factor for late recurrence but not for overall survival of early stage hepatocellular carcinoma. Tumor Biol. 36, 4993–5000 (2015). https://doi.org/10.1007/s13277-015-3150-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3150-7

Keywords

Search

Navigation