Inhibition Of Vascular Endothelial Growth Factor Over-expression On Influences Of Malignant Transformation Of Hepatocytes By Thalidomide

【Objective】Hepatocellular carcinoma (HCC) is characterized by multicause and obvious multistage, multifocus process of tumor progression. Development of HCC is related intimately with over- expression and signal transduction of many cellular factors. The aim of the present study was to investigate the dynamic expression and alteration of vascular endothelial growth factor (VEGF) during HCC development and the influences on malignant transformation of hepatocytes through the intervention of thalidomide for exploring its clinical values and anti-angiogenic therapeutics of HCC.【Methods】Rat hepatoma models were induced with 2-fluorenyl acetamide (2-FAA) on male Sprague-Dawly (SD) rats, thalidomide was administered intragastrically (100 mg/kg body weight) to intervene the progress of hepatoma. A part of rats of each group were sacrificed fortnightly interval to the twelfth week. Morphological changes were observed by pathological examinations (HE staining). The VEGF expressions in liver tissues and sera were detected by enzyme linked immunosorbent assay (ELISA). The VEGF expressions in rat or human liver tissues were semi-quantitatively analyzed by immunohistochemistry. The relationship between VEGF expression and the clinical pathological characteristics in human HCC and their non-cancerous tissues were analyzed and its clinical values were explored in the present study.【Results】Histological examinations evidenced that hepatocytes in rats fed with 2-FAA showed vacuole-like denaturations at the early stages, then dysplastic nodules appeared at the middle stages, and finally progressed to tubercles of cancerous nest, all of which were highly differentiated HCC. It was found that thalidomide can repress the morphologic change of liver cells. There were only punctiform denaturations at the early and middle stages; Nodosity hyperplasy and minority atypical hyperplasia were found at the finally stages. The results of immunohistochemistry and western blot demonstrated that the VEGF level of liver tissues in hepatoma rats was significantly higher than those in normal ones, and the VEGF level of liver tissues in inducing hepatoma group was higher than those in thalidomide group (χ2 = 8.025,P < 0.05). An increasing tendency of liver nucleus VEGF protein was found from normal liver to precancerous to cancerous tissues during rat hepatoma development by ELISA (P < 0.01). The levels of VEGF in livers and sera in hepatoma rats were significantly higher than those in normal ones(P < 0.05). The expressions of VEGF in human HCC tissues were higher ( P < 0.01 ) than that in their non-cancerous tissues. Serum VEGF in HCC was significantly higher than that in chronic hepatitis or cirrhosis or controls ( P < 0.01 ).【Conclusions】The overexpression of hepatic VEGF is observed during HCC development. Chemical intervene with thalidomide can decrease VEGF expression, and inhibit the development of hepatoma, suggesting that VEGF is expected to be a new molecular target of hepatoma gene therapy.