BACKGROUND: Hepatic hypoxia-inducible factor-1 (HIF-1) is activated in the progression of hepatocellular carcinoma (HCC). This study aimed to investigate the dynamic alterations of HIF-1α and its gene expression so as to explore the relationship between HIF-1α expression and hepatocarcinogenesis at the early stage of HCC.
METHODS: A hepatoma model was made with 2-fluorenyl-acetamide (2-FAA) in male Sprague-Dawley rats. Morpho-logical changes of rat hepatocytes were assessed pathologically (HE staining). The dynamic expression of hepatic and circulating HIF-1α was quantitatively analyzed by ELISA. The gene fragments of hepatic HIF-1α mRNA were amplified by RT-PCR and confirmed by sequencing. The cellular distribution of hepatic HIF-1α expression was confirmed by immunohistochemistry.
RESULTS: Histological examination confirmed granule-like degeneration to atypical hyperplasia and HCC development in rat hepatocytes and progressive increases in the levels of hepatic and circulating HIF-1α and its gene expression during the course. The levels of HIF-1α expression in the liver and blood of rats with hepatoma were significantly higher than those in normal rats and those with degeneration. Immunohistochemical analysis confirmed the positive expression and hepatocyte distribution of HIF-1α in the development of rat hepatoma. A positive relationship was found between HIF-1α expression in the liver and blood (P<0.01).
CONCLUSIONS: The above observations support the hypothesis that the overexpression of HIF-1α and its gene are closely associated with the malignant transformation of hepatocytes and play an important role at the stage of hepatocarcinogenesis.