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Loss of p16 Contributes to p27 Sequestration by Cyclin D₁-Cyclin-dependent Kinase 4 Complexes and Poor Prognosis in Hepatocellular Carcinoma

Division of Bio-systemic Gastroenterology, Department of Regenerative and Transplant Medicine, Course of Biological Functions and Medical Control, Niigata University Graduate School of Medicine and Dental Science, Asahimachi-dori 1-757, Niigata City 951-8510, Japan

Purpose: p27^Kip1 (p27) might act as an adverse prognostic marker for various types of cancers. However, its clinical usefulness remains uncertain, because it is sometimes overexpressed in aggressive types.

Experimental Design: To precisely evaluate the practical significance of p27 in hepatocellular carcinoma (HCC), we immunohistochemically compared the level of p27 expression with Ki-67 labeling in 74 HCCs and focused on tumors in which cell proliferation increased despite a high level of p27 expression. We then analyzed the status of p27 and related cell-cycle regulators using kinase and immunoprecipitation assays, Western blotting, and methylation-specific PCR to understand the rationale for the functional inactivation of p27 in HCC. We also evaluated relationships between the key biological characteristics of HCC and survival.

Results: Immunohistochemical studies showed that 40 (54%) of 74 HCCs expressed high levels of p27 (>50% of the tumor cells). Of these, the Ki-67 labeling index was low (<20%) in 26 (65%) and high (>20%) in 14 (35%). Increased proliferative activities were closely correlated with elevated kinase activities, sequestration of p27 protein, and p16 gene methylation. The association between a loss of p16 and poor prognosis was significant when p27 expression was high (P < 0.01).

Conclusions: The loss of p16 appears to be closely related to the functional inactivation of p27, and assessment of p16 status may be useful for a precise prognostic prediction of individuals with HCC expressing high levels of p27.

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