| Budget Amount *help |
¥8,100,000 (Direct Cost: ¥8,100,000)
Fiscal Year 2004: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2003: ¥4,200,000 (Direct Cost: ¥4,200,000)
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| Research Abstract |
Hepatocellular carcinoma (HCC) is the fifth most common malignant disorder and causes about 1 million deaths a year worldwide. Hepatocellular carcinoma is more common in Asia and Africa. About 80% of patients with HCC also have liver cirrhosis. In this study, we intend to delineate the rapid response of the anti-proliferative action of IFN-α via the MAPK pathway in human hepatocellular carcinoma cell lines. And using siRNA technology, we investigated the enhancement of phosphorylation of MEK and ERK and blocked the inhibition of phosphorylation of MEK and ERK and downstream gene activation and suppression pathway by microarray. The potential anti-proliferation effict of interferonalpha (IFN-α) against hepatocellular carcinoma and its growth inhibitory mechanisms remain poorly understood. In this study, we delineated the rapid response of the anti-proliferative action of IFN-α via the MAPK pathway in human hepatocellular carcinoma cell lines HepG2, Hep3B, HuH7, and PLC/PRF/5. We found that PLC/PRF/5, which had the most abundant expression of IFN-α receptors, was highly sensitive to growth inhibition by IFN-α. IFN-α retarded G1/S transition with no evidence of apoptosis. IFN-α suppressed the phosphorylation of both extracellular signal-regulated kinase (ERK) and mitogen-activated ERK-regulating kinase (MEK), but not Raf, within 5 min. Knockdown of STAT1 and JAK1 suppressed the reduction of phosphorylation both of ERK and MEK and diminished the growth inhibition by IFN-α. These results suggest that IFN-α induces rapid antiproliferative signaling via JAK/STAT pathway downstream of IFN-α receptors and may inhibit the growth stimulation signaling by cross-talk with the MEK/ERK pathway. By expression profiling, we identified common down regulated or up-regulated genes and their transcriptional regulatory elements.
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