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
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
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
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
Beasley RP, Hwang L-Y, Lin C-C and Chien C-S (1981) Hepatocellular carcinoma and hepatitis B virus. Lancet 11: 1129–1133
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
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
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
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
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
Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R and Soltoff S (1991) Oncogenes and signal transduction. Cell 64: 281–302
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
Chomczynski P and Sacchi N (1987) Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159
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
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
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
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
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
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
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
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
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
Ito Y,, Takeda T, Sasaki Y, Sakon M, Yamada T, Ishiguro S, Imaoka S, Tsujimoto M, Higashiyama S, Monden M and Matsuura T Expression and clinical significance of the erbB family in intrahepatic cholangiocellular carcinoma. Pathology Res Pract,
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
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
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
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
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
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
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
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
Lee CS and Pirdas A (1995) Epidermal growth factor receptor immunoreactivity in gallbladder and extrahepatic biliary tract tumours. Path Res Pract 191: 1087–1091
Liver Cancer Study Group of Japan (1992) The General Rules for the Clinical and Pathological Study of Primary Liver Cancer. Kanehara Press: Tokyo
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
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
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
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
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
Sambrook J, Fritsch EF and Maniatis T (1989) Molecular cloning: a laboratory manual (Edn 2.). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press
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
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
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
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
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
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
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 α, neuregulin-1 β, and betacellulin, in normal endometrium and endometrial cancer. Clinical Cancer Res 5: 2877–2883
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
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
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
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
Ullrich A and Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61: 203–212
Uwaifo AO and Bababunmi EA (1984) Liver carcinogenesis in tropical Africa. IARC Sci Publ 63: 59–88
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
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
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Ito, Y., Takeda, T., Sakon, M. et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer 84, 1377–1383 (2001). https://doi.org/10.1054/bjoc.2000.1580
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2000.1580
Keywords
This article is cited by
-
LHPP suppresses proliferation, migration, and invasion in hepatocellular carcinoma and pancreatic cancer by inhibiting EGFR signaling pathway
Medical Oncology (2023)
-
CRNDE acts as an epigenetic modulator of the p300/YY1 complex to promote HCC progression and therapeutic resistance
Clinical Epigenetics (2022)
-
EGFR inhibition reverses resistance to lenvatinib in hepatocellular carcinoma cells
Scientific Reports (2022)
-
Prediction of hepatocellular carcinoma risk in patients with chronic liver disease from dynamic modular networks
Journal of Translational Medicine (2021)
-
Elafin promotes tumour metastasis and attenuates the anti-metastatic effects of erlotinib via binding to EGFR in hepatocellular carcinoma
Journal of Experimental & Clinical Cancer Research (2021)