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KMID : 0357919990330111009
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Korean Journal of Pathology
1999 Volume.33 No. 11 p.1009 ~ p.1023
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Immunohistochemical Analysis of Transforming Growth Factor (TGF)-β1 and TGF-β Receptor II and Quantitative Analysis of TGF-β1 mRNA during Multistep Hepatocarcinogenesis Induced by Diethylnitrosamine in Sprague-Dawley Rats
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Cho Mee-Yon
Lee Ju-Han
Kang Yong-Koo
Won Nam-Hee
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Abstract
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Transforming growth factor (TGF)-β1 plays an important role in hepatocarcinogenesis and has been described as a useful tumor marker and one of the poor prognostic indicators in patients with hepatocellular carcinoma (HCC). To investigate the role and cellular localization of TGF-β1 during multistep hepatocarcinogenesis we performed a quantitative analysis of TGF-β1 mRNA and immunohistochemical expression of TGF-β1 and TGF-β receptor II (TGF-βrII) in female Sprague-Dawley rats. The experimental groups included neoplastic lesions produced by Solt-Farber’s protocol, regenerating liver after partial hepatectomy, and normal control. Quantitative change of TGF-β1 mRNA was analysed by competitive reverse-transcription polymerase chain reaction (RT-PCR). TGF-β1 protein and TGF-βrII expression were evaluated by immunohistochemical stain. The discrete tumor nodules were detected on 14th day and then increased in number and size. Three HCCs were induced on 8th or 9th month. RT-PCR demonstrated TGF-β1 mRNA band in all examples of the normal and regenerating liver, nodules and HCCs. Competitive RT-PCR displayed higher TGF-β1 mRNA in nodules, HCCs and regenerating liver than in normal controls. Hepatocytes from control and regenerating livers showed weak immunoreactivity for TGF-β1. In contrast, the cytoplasm of hepatocytes of nodules in 7th, 8th and 9th month and HCCs were intensely stained for TGF-β1. Some sinusoidal cells showed immunoreactivity for TGF-β1 in all experimental groups. In early phase of carcinogenesis, the cytoplasm of hepatocytes in liver of 12h, 1d and 3d showed transiently increased immunoreactivity for TGF-β1 and The immunoreactivity decreased thereafter. TGF-β1 mRNA was also detected in the neoplastic hepatocytes by in-situ hybridization. Although TGF-βrII expression was correlated with TGF-β1 immunoreactivity during early phase of carcinogenesis, hepatocytes in most nodules in 7th, 8th, 9th month and carcinomas showed decreased or little immunoreactivity for TGF-βrII. Based on the above results, it is concluded that TGF-β1 expression increases not only in precancerous nodules but also in HCCs and its increase seems to be correlated with decrease or loss of TGF-βrII expression although its mechanism remains unclear. Hepatocytes may be a major cellular source of TGF-β1 during hepatocarcinogenesis.
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KEYWORD
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TGF-β1, TGF-β receptor II, Hepatocarcinogenesis, Competitive RT-PCR
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