Proteome analysis in normal liver, chronic hepatitis, liver cirrhosis and hepatocellular carcinoma-For a novel diagnosis, treatment and protection of hepatocellular carcinoma

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Cyclins, cyclin-dependent kinases (Cdks), and Cdk inhibitors (CdkIs) are frequently altered in human cancer. p 18^<INK4C>, a member of the INK4 family among CdkIs, is a potential tumor suppressor gene product. However, the expression of p 18^<INK4C> in hepatocellular carcinoma (HCC) remains unknown. The aim of this study was to examine the expression of p18^<INK4C> in various liver diseases including HCC and to assess its clinical significance in HCC. To that end, we examined the expression of p 18^<INK4C> by immunohistochemistry in various liver diseases including 51 HCCs, and also studied the relationship among p 18^<INK4C> expression, the phosphorylation of retinoblastoma protein (pRb), and the activity level of Cdk4 and Cdk6. Immunohistochemical analysis revealed the frequent loss of p18^<INK4C> expression in HCC, especially in poorly differentiated HCC. The loss of p18^<INK4C> expression was shown to be associated with a poor prognosis as compared with that associated with p18^<INK4C>-positivity. Further, the kinas activity of Cdk4 was found to be higher in p18^<INK4C>-negative HCCs than in p 18^<INK4C>-positive HCCs. However, the level of Cdk6 activity was similar in the two groups of HCCs. In p18^<INK4C>-positive HCCs, p18^<INK4C> dominantly interacted with Cdk4 rather than with Cdk6. pRb phosphorylated at Ser 780 was detected more frequently in p18^<INK4C>-negative than in p 18^<INK4C>-positive HCCs. These data suggest that the loss of p18^<INK4C> expression may play a role in the differentiation and development of HCC through the upregulation of Cdk4 activity.