Regular Article

British Journal of Cancer (2001) 84, 1377–1383. doi:10.1054/bjoc.2000.1580 www.bjcancer.com
Published online 15 May 2001

Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma

Y Ito1,2, T Takeda1, M Sakon3, M Tsujimoto4, S Higashiyama5, K Noda6, E Miyoshi6, M Monden3 and N Matsuura2

  1. 1Department of Surgery, Osaka Seamen's Insurance Hospital, 1-8-30, Chikko, Minato-ku, Osaka 552-0021, Japan
  2. 2Department of Pathology, 10–31, Kitayama-cho, Tennoji-ku, Osaka 543, Japan
  3. 3Department of Surgery II, 10–31, Kitayama-cho, Tennoji-ku, Osaka 543, Japan
  4. 4Department of Pathology, Osaka Police Hospital, 10–31, Kitayama-cho, Tennoji-ku, Osaka 543, Japan
  5. 5Department of Biochemistry, School of Allied Health Science, Osaka University Faculty of Medicine, 1–7, Yamadaoka, Suita, Osaka, 565 0871, Japan
  6. 6Department of Biochemistry, Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka, 565 0871, Japan

Received 11 May 2000; Revised 5 October 2000; Accepted 18 October 2000.

Top

Abstract

In order to elucidate the clinical significance of the erbB family, epidermal growth factor receptor (EGF-R), c-erbB-2, c-erbB-3 and c-erbB-4 in hepatocellular carcinoma (HCC), we investigated the expression of these proteins by means of immunohistochemistry for HCC as well as adjacent noncancerous lesions. EGF-R was expressed in 68% of the HCC examined and showed correlation with the proliferating activity, stage, intrahepatic metastasis and carcinoma differentiation. c-erbB-2 was expressed in only 21% of the cases and showed no relationships with the clinicopathological parameters. c-erbB-3 protein was observed in 84% of the HCC and 38.1% of the noncancerous lesions. Its expression in HCC was equal to or greater than noncancerous lesions in 90.5% of the cases, and was related to the stage, portal invasion, cell proliferating activity, tumour size, intrahepatic metastasis and carcinoma differentiation. c-erbB-4 protein was expressed in 61.0% of HCC and in as much as 86.1% of the noncancerous lesions. Unlike the expression of c-erbB-3, that of c-erbB-4 in HCC was less than that of the adjacent noncancerous lesions in 51.2% of the cases. No statistical significance could be established between this protein expression in HCC and clinicopathological features. EGF-R and c-erbB-3 affected disease-free survival, but were not recognized as independent prognostic factors by multivariate analysis. The present study suggests that, of the four receptors, EGF-R and c-erbB-3 play important roles in the progression of HCC. © 2001 Cancer Research Campaign

Keywords:

EGF-R, c-erbB-2, c-erbB-3, c-erbB-4, hepatocellular carcinoma, immunohistochemistry

Top

References

  1. Bacus SS, Chin D, Yarden Y, Zemick CR and Stern DF (1996) Type 1 receptor tyrosine kinases are differentially phosphorylated in mammary carcinoma and differentially associated with steroid receptors. Am J Pathol 148: 549–558 | PubMed | ISI | ChemPort |
  2. Baulida J, Kraus MH, Alimandi M, Di Fiore PP and Carpenter G (1996) Al Erb B receptors other than the epidermal growth factor receptor are endocytosis impaired. J Biol Chem 271: 5251–5257 | Article | PubMed | ISI | ChemPort |
  3. Beasley RP, Hwang L-Y, Lin C-C and Chien C-S (1981) Hepatocellular carcinoma and hepatitis B virus. Lancet 11: 1129–1133
  4. Berchunk A, Kamel A, Whitaker R, Kerns B, Olt G, Kinney R, Soper JT, Dodge R, Clarke-Pearson DL and Marks P (1990) Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res 50: 4087–4091 | PubMed | ISI | ChemPort |
  5. Bobrow LG, Millis RR, Happerfield LC and Gullick WJ (1997) c-erbB-3 protein expression in ductal carcinoma in situ of the breast. Eur J Cancer 33: 1846–1850
  6. Bodey B, Bodey B Jr, Groger AM, Luck JV, Siegel SE, Taylor CR and Kaiser HE (1997) Clinical and prognostic significance of the expression of the c-erbB-2 and c-erbB-3 oncoproteins in primary and metastatic malignant melanomas and breast carcinomas. Anticancer Res 17: 1319–1330 | PubMed | ISI | ChemPort |
  7. Borg A, Tandom AK, Sigurdsson H, Clark GM, Ferno M, Fuqua SA, Killander D and McGuire WL (1990) HER-2/neu amplification predicts poor survival in node-positive breast cancer. Cancer Res 50: 4332–4337 | PubMed | ISI | ChemPort |
  8. Brunt EM and Swanson PE (1992) Immunoreactivity for c-erbB-2 oncopeptide in benign and malignant diseases of the liver. Am J Clin Pathol 97: S53–61
  9. Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R and Soltoff S (1991) Oncogenes and signal transduction. Cell 64: 281–302 | Article | PubMed | ISI | ChemPort |
  10. Chang C-P, Lazar CS, Walsh BJ, Komuro M, Collawn JF, Kuhn LA, Tainer JA, Trowbridge IS, Farguhar MG, Rosenfeld MG, Wiley HS and Gill GN (1993) Ligand-induced internalization of the epidermal growth factor receptor is mediated by multiple endocytic codes analogous to the tyrosine motif found in constitutively internalized receptors. J Biol Chem 268: 19312–19320 | PubMed | ISI | ChemPort |
  11. Chomczynski P and Sacchi N (1987) Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159 | Article | PubMed | ISI | ChemPort |
  12. Chow N-H, Liu H-S, Yang H-B, Chan S-H and Su I-J (1997) Expression patterns of erbB receptor family in normal urothelium and transitional cell carcinoma. Virchows Arch 430: 461–466
  13. Collier JD, Guo K, Mathew J, May FEB, Bennett MK, Corbett IP, Bassendine MF and Burt AD (1992) c-erbB-2 oncogene expression in hepatocellular carcinoma and cholangiocarcinoma. J Hepatol 14: 377–380 | PubMed |
  14. Dugan MC, Dergham ST, Kucway R, Siingh K, Biernat L, Du W, Vaitkevicius VK, Crissman JD and Sarkar FH (1997) HER-2/neu expression in pancreatic adenocarcinoma: relation to tumor differentiation and survival. Pancreas 14: 229–236 | PubMed | ISI | ChemPort |
  15. Elenius K, Paul S, Allison G, Sun J and Klagsbrum M (1997) Activation or HER4 by heparin binding EGF-like growth factor stimulates chemotaxis but not proliferation. EMBO J 16: 1268–1278 | Article | PubMed | ISI | ChemPort |
  16. Freiss H, Fukuda A, Tang W-H, Tang W-H, Eichenberger A, Furlan N, Zimmermann A, Korc M and Buchler MW (1999) Concomitant analysis of the epidermal growth factor receptor family in esophageal cancer: overexpression of epidermal growth factor receptor mRNA but not of c-erbB-2 and c-erbB-3. World J Surg 23: 1010–1018 | Article | PubMed | ISI | ChemPort |
  17. Haugen DRF, Akslen LA, Varhaug JE and Lillehaug JR (1996) Expression of c-erbB-3 and c-erbB-4 proteins in papillary thyroid carcinomas. Cancer Res 56: 1184–1188 | PubMed | ISI | ChemPort |
  18. Haussler O, Epstein JI, Amin MB, Heitz PU and Hailemariam S (1999) Cell proliferation, apoptosis, oncogene, and tumor suppressor gene status in adenosis with comparison to benign prostatic hyperplasia, prostatic intraepithelial neoplasia, and cancer. Human Pathol 30: 1077–1086 | ISI |
  19. Ibrahim SO, Vasstrand EN, Liavaag PG, Johannessen AC and Lillehaug JR (1997) Expression of c-erbB proto-oncogene family members in squamous cell carcinoma of the head and neck. Anticancer Res 17: 4539–4546 | PubMed | ChemPort |
  20. Ito Y, Matsuura N, Sakon M, Takeda T, Umeshita K, Nagano H, Nakamori S, Dono K, Tsujimoto M, Nakahara M, Nakao K and Monden M (1999) Both cell proliferation and apoptosis significantly predict shortened disease-free survival in hepatocellular carcinoma. Br J Cancer 81: 747–751 | Article | PubMed | ISI | ChemPort |
  21. Ito Y, , Takeda T, Sasaki Y, Sakon M, Yamada T, Ishiguro S, Imaoka S, Tsujimoto M, Higashiyama S, Monden M and Matsuura TExpression and clinical significance of the erbB family in intrahepatic cholangiocellular carcinoma. Pathology Res Pract,
  22. Kameda T, Yasui W, Yoshida K, Tsujino T, Nakayama H, Ito M, Ito H and Tahara E (1990) Expression of ERBB2 in human gastric carcinomas: relationship between p185ERBB2 expression and the gene amplification. Cancer Res 50: 8002–8009 | PubMed | ISI | ChemPort |
  23. Kapitanovic S, Radosevic S, Slade N, Kapitanovic M, Andelinovic S, Ferencic Z, Tavassoli M, Sparenti S, Pavelic K and Sparenti R (2000) Expression of erbB-3 protein in colorectal adenocarcinoma: correlation with poor survival. J Cancer Res Clin Oncol 126: 205–211 | Article | ChemPort |
  24. Kern JA, Schwartz DA, Nordberg JE, Weiner DB, Greene ML, Torney L and Robinson RA (1990) p185neu expression in human lung adenocarcinomas predicts shortened survival. Cancer Res 50: 5184–5187 | PubMed | ISI | ChemPort |
  25. Kew TY, Bell JA, Pinder SE, Denley H, Srinivasan R, Gullick WJ, Nicholson RI, Blamey RW and Ellis IO (2000) c-erbB-4 protein expression in human breast cancer. Br J Cancer 82: 1163–1170 | Article | PubMed | ISI | ChemPort |
  26. Kim HH, Sierke SL and Koland JG (1994) Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product. J Biol Chem 269: 24747–24755 | PubMed | ISI | ChemPort |
  27. Kira S, Nakanishi T, Suemori S, Kitamoto M, Watanabe Y and Kajiyama G (1997) Expression of transforming growth factor alpha and epidermal growth factor receptor in human hepatocellular carcinoma. Liver 17: 177–182 | PubMed | ChemPort |
  28. Komurasaki T, Toyoda H, Uchida D and Morimoto S (1997) Epiregulin binds to epidermal growh factor receptor and ErbB-4 and induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4. Oncogene 15: 2841–2848 | Article | PubMed |
  29. Kraus MH, Issing W, Miki T, Popescu NC and Aaronson SA (1989) Isolation and characterisation of c-erbB-3, a third member of the erbB/epidermal growth factor receptor family; evidence of over expression in a subset of human mammary tumours. Proc Natl Acad Sci USA 86: 9193–9197 | Article | PubMed | ChemPort |
  30. Lee CS and Pirdas A (1995) Epidermal growth factor receptor immunoreactivity in gallbladder and extrahepatic biliary tract tumours. Path Res Pract 191: 1087–1091
  31. Liver Cancer Study Group of Japan (1992) The General Rules for the Clinical and Pathological Study of Primary Liver Cancer. Kanehara Press: Tokyo
  32. Nakopoulou L, Stefanaki K, Filaktopoulos D and Giannopoulou I (1994) C-erb-B-2 oncoprotein and epidermal growth factor receptor in human hepatocellular carcinoma: An immunohistochemical study. Histol Histopath 9: 677–682
  33. Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, Lavi S, Sager R, Ratzkin BJ, Sela M and Yarden Y (1996) Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J 15: 2452–2467 | PubMed | ChemPort |
  34. Plowman GD, Culouscou J-M, Whitney GS, Green JM, Carlton GW, Foy L, Neubauer MG and Shoyab M (1993) Ligand-specific activation of HER4/p180, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci USA 90: 1746–1750 | Article | PubMed | ChemPort |
  35. Riese DJ, Bermingham Y, van Raaij TM, Buckely S, Plowman GD and Stern DF (1996) Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin. Oncogene 12: 345–353 | PubMed | ISI | ChemPort |
  36. Saito I, Miyamura T, Ohbayashi A, Harada H, Katayama T and Kikuchi S (1990) Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Nathl Acad Sci USA 87: 6547–6549
  37. Sambrook J, Fritsch EF and Maniatis T (1989) Molecular cloning: a laboratory manual (Edn 2.). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press
  38. Sanidas EE, Filipe MI, Linehan J, Lemoine NR, Gullick WJ, Rajkumar T and Levison DA (1993) Expression of the c-erbB-3 gene product in gastric cancer. Int J Cancer 54: 935–940 | Article | ChemPort |
  39. Sasaki K, Murakami T and Kawasaki M (1987) The cell cycle associated change of the Ki-67 reactive nuclear antigen expression. J Cell Physiol 133: 579–584 | Article | PubMed | ISI | ChemPort |
  40. Shintani S, Funayama T, Yoshihama Y, Alcalde R, Ootsuki K, Terakado N and Matsumura T (1995) Expression of c-erbB family gene products in adenoid cystic carcinoma of salivary glands: an immunohistochemical study. Anticancer Res 15: 2623–2626 | PubMed | ISI | ChemPort |
  41. Simpson BJB, Phillips HA, Lessells AM, Langdon SP and Miller WR (1995) c-erbB growth-factor-receptor proteins in ovarian tumours. Int J Cancer 64: 202–206 | Article | PubMed | ISI | ChemPort |
  42. Soltoff SP, Carraway KL, Prigent SA, Gullick WG and Cantley LC (1994) ErbB3 is involved in activation of phosphaidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol 14: 3550–3558 | PubMed | ISI | ChemPort |
  43. Srinivasan R, Poulsom R, Hurst HC and Gullick W (1998) Expression of the c-erbB-4/HER-4 protein and mRNA in normal human fetal and adult tissues and in a survey of the nine solid tumour types. J Pathol 185: 236–245 | Article | PubMed | ISI | ChemPort |
  44. Srinivasan R, Benton E, McCormick F, Thomas H and Gullick WJ (1999) Expression of the c-erbB-3/HER-3 and c-erbB-4/HER-4 growth factor receptors and their ligands, neuregulin-1 alpha, neuregulin-1 beta, and betacellulin, in normal endometrium and endometrial cancer. Clinical Cancer Res 5: 2877–2883
  45. Srinivasan R, Gillett CE, Barnes DM and Gullick WJ (2000) Nuclear expression of the c-erbB-4/HER-4 growth factor receptor in invasive breast cancers. Cancer Res 60: 1483–1487 | PubMed | ISI | ChemPort |
  46. Suo Z, Emilsen E, Tveit KM and Nesland JM (1998) Type 1 protein tyrosine kinases in benign and malignant breast lesions. Histopathology 33: 514–521 | Article | PubMed | ISI | ChemPort |
  47. Terada T, Ashida K, Endo K, Horie S, Maeta H, Matsunaga Y, Takashima K, Ohta T and Kitamura Y (1998) c-erbB-2 protein is expressed in hepatolithiasis and cholangiocarcinoma. Histopathology 33: 325–331
  48. Travis A, Pinder SE, Robertson JFR, Bell JA, Wencyk P, Gullick WJ, Nicholson RI, Poller DN, Blamey RW, Elston CW and Ellis IO (1996) C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators. Br J Cancer 74: 229–233 | PubMed | ISI | ChemPort |
  49. Ullrich A and Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61: 203–212 | Article | PubMed | ISI | ChemPort |
  50. Uwaifo AO and Bababunmi EA (1984) Liver carcinogenesis in tropical Africa. IARC Sci Publ 63: 59–88
  51. Yang J-L, Yu Y, Markovic B, Russell PJ and Crowe PJ (1997) Overexpression of c-erbB-2 mRNA and/or c-neu oncoprotein is a predictor for metastases from colorectal cancer. Anticancer Res 17: 1023–1026 | PubMed |
  52. Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Brush J and Godowski PJ (1997) Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4. Proc Natl Acad Sci USA 94: 9562–9567 | Article | PubMed | ChemPort |