| Research Abstract |
Several liver enriched transcription factors were identified and the regulation of their expressions has been well known. We showed that HNF-1a expression decreased, although HNF-1β remained unchanged, during dedifferentiation from well differentiated hepatocellular carcinoma (HCC) to poorly differentiated HCC.We also characterized an undifferentiated HCC cell-line, referred to as ETK-1, which has the potency of bilateral differentiation, like liver stem cell, into both hepatocyte, referred to as MEK, and biliary epithelial cell, referred to as NEC.ETK-1 cell expressed neither HNF-1α nor HNF-4. MEK cell showed expression of both HNF-1α and HNF-4. NEC expressed only HNF-4, but not HNF-1α. ETK-1 and NEC had no expression of liver specific genes, such as transthyretin and albumin, AFP and so on, although MEK expressed all sets of liver specific genes. Our study focused on the mechanism how NEC has no expression of liver specific genes or HNF-1α in spite of its expression of HNF-4. Fluores
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cent microscopic observations of NEC cell demonstrated that the HNF-4 located in the cytoplasm, not in the nucleus. The lack of transference of HNF-4 from cytoplasm into nucleus seemed to induce its functional defect as a transcription regulator. Such abnormal distribution of nuclear transcription factors might be an important process in dedifferentiation of HCC.We also analysed the signal transduction molecules inplicated in liver enriched transcription regulation during dedifferentiation of HCC.Immunohistochemical and western- and northern-blot analysis of surgically hepatectomized HCC tissues showed that overexpression of SAP-1, a human transmembrane-type protein tyrosine phosphatase in well differentiated HCC and its expression decreased during dedifferentiation of HCC.Induction of overexpression of SAP-1 in poorly differentiated HCC cell-line by transgene caused redifferentiation of HCC, and suppressed cellular proliferation and invasion. SAP-1 may be a molecule implicated in evolution and metastasis of HCC through hepatocytic differentiation. Less
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