Involvement of ATBF1 in liver regeneration and hepatocarcinogenesis

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AT motif-binding factor 1 (ATBF1) cDNA was first isolated from HuH-7 human hepatoma cells based on the ability of its products to bind to an AT-rich element in the enhancer of the human alpha-fetoprotein gene. ATBF1 protein belongs to a family of transcription factors containing both homeodomain and zinc finger motifs. Expression of ATBF1 is induced during neuronal and myogenic differentiation, and also observed in immature cells at the base of villi. This study aims to clarify a role of ATBF1 in liver regeneration and hepatocarcinogenesis. First, we have established real-time PCR to measure expression level of ATBF1 mRNA, and examined sequential changes in ATBF1 expression during proliferation of primary cultured rat hepatocytes treated with hepatocyte growth factor. Expression of ATBF1 was suppressed 6 hours after HGF treatment, while cyclin D1 expression was stimulated. To examine ATBF1 expression in hepatic progenitor cells, rats were administered 2-acetylaminofluorene (2-AAF) five times a week for two weeks, followed by partial hepatectomy (PH). In this 2-AAF/PH model, hepatic progenitor cells, so called "oval cells", are observed alongside of portal areas, and HGF stimulates proliferation and hepatic differentiation of these cells. In mature hepatocytes, ATBF1 expression was immunohistochemically observed in the nucleus eight days after PH, whereas ATBF1 was detected in both nucleus and cytoplasm. Additionally, Although HGF treatment decreased nuclear expression of ATBF1 in mature hepatocytes, and ATBF1 expression in the cytoplasm of oval cells was decreased by this treatment. These results suggest that HGF treatment stimulated proliferation and hepatic differentiation of oval cells, and that proliferation of oval cells gradually terminated and differentiation to mature hepatocytes was induced. ATBF1 may play an important role in proliferation or differentiation of hepatic progenitor cells via its intracellular localization.