Expression of ErbB receptor proteins and TGF-alpha during diethylnitrosamine-induced hepatocarcinogenesis in the rat liver.
OBJECTIVE
ErbB receptor proteins are transmembrane tyrosine kinase receptors; when they are activated by interaction with ligands, they generate diverse cellular responses, especially during lesion development and progression to cancer. In this study the expression of ErbB receptors and TGF-alpha were investigated using an experimental cirrhosis rat model giving rise to hepatocellular neoplasms, similar to human liver diseases.


METHODS
Fifty three male rats received intraperitoneal injection of diethylnitrosamine (DEN, 50 mg/kg), weekly for 18 weeks. Until the eighth week, two rats were sacrificed every two weeks and from the tenth to the eighteenth week, five rats were sacrificed weekly. Grossly, dyschromatic and dysmorphic nodules were counted and categorized into three groups: N1/N2/N3: 3 mm < or = x < 5 mm/5 mm < or = x < 10 mm/x > or = 10 mm in diameter. All nodules were examined, histologically. Antibodies for GSTp, TGF-alpha, EGF-R, ErbB2, ErbB3 and ErbB4 were used for immunohistochemistry.


RESULTS
The onset of cirrhoses was noted from the twelfth week. Preneoplastic foci, hepatocellular adenomas (HCA) and hepatocellular carcinomas (HCC) were noted from the second, eleventh and fifteenth week, respectively. The nodules (N1/N2/N3: 397/258/64) included regenerating nodule; RN (N1/N2/N3: 72.3%/15.9%/0%), HCA (N1/N2/N3: 27.2%/82.2%/7.6%) and HCC (N1/N2/N3: 0.5%/ 1.9%/92.4%). EGF-R was expressed in 12.5% of RN, 64.7% HCA and 75.2% HCC. TGF-alpha was expressed in 92.4% of RN, 91.3% HCA and 93.2% HCC. Sixty eight percent of TGF-alpha expressing nodules showed concurrent EGF-R expression. ErbB2 was expressed in 83.6% of RN, 72.9% HCA and 88.7% HCC. ErbB4 was expressed in 95.2% of RN, 86.3% HCA and 62.5% HCC.


CONCLUSIONS
Increased expression of EGF-R and decreased expression of ErbB4, might be related with tumor progression during DEN-induced hepatocarcinogenesis.
Lee
Tae Yeong
TY
Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.
Kim
Kyoung-Tae
KT
Han
Sang-Young
SY
D018248:Adenoma, Liver Cell / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004052:Diethylnitrosamine; D066246:ErbB Receptors / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D066247:Receptor, ErbB-4; D016211:Transforming Growth Factor alpha / Q000378:metabolism*
D004052:Diethylnitrosamine; D066246:ErbB Receptors; D005982:Glutathione Transferase; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D016211:Transforming Growth Factor alpha; C587689:ERBB4 protein, human; C587691:Erbb4 protein, rat