Expression of Pirh2, a p27^Kip1 ubiquitin ligase, in hepatocellular carcinoma: correlation with p27^Kip1 and cell proliferation

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• 作者：Xiaodong Huang MM^a ; ¹ ; Xiaoli Qian MM^b ; ¹ ; Chun Cheng MM^a ; Song He MM^a ; Linlin Sun PhD^b ; Qing Ke MM^b ; Li Zhang MM^b ; Xia Pan MM^b ; Fei He MM^b ; Qiuhong Wang MM^b ; Jie Meng MM^b ; Runzhou Ni MD^a ; ^nirz@163.com ; Aiguo Shen PhD^a ; ^{shen_aiguo@yahoo.com}
• 关键词：Pirh2 ; p27^Kip1 ; Hepatocellular carcinoma ; Cell proliferation
• 刊名：Human Pathology
• 出版年：2011
• 出版时间：April 2011
• 年：2011
• 卷：42
• 期：4
• 页码：507-515
• 全文大小：1259 K

文摘

Summary

p53-Induced ring-H2 protein (Pirh2), a recently identified ubiquitin–protein ligase, interacts with p27^Kip1 to promote ubiquitination of p27^Kip1 independently of p53. High Pirh2 and low p27^Kip1 immunoreactivity are associated with a poor prognosis in several cancers, including resistant phenotypes. In the present study, we investigated the role of Pirh2 and p27^Kip1 in human hepatocellular carcinoma (HCC) progression. Immunohistochemical analysis was performed on formalin-fixed paraffin sections of 87 specimens. Statistical analysis showed that expression of Pirh2 was negatively related to p27^Kip1 expression (r = 0.787; P < .05), and Pirh2 expression correlated significantly with histologic grade (P < .001), venous invasion (P = .004), tumor size (P = .024), and the presence of multiple tumor-bearing lymph nodes (P = .017), whereas p27^Kip1 expression correlated significantly with histologic grade (P < .001), venous invasion (P = .048), and cirrhosis (P = .028). By Kaplan-Meier analysis, the survival curves of low versus high expressers of Pirh2 and p27^Kip1 showed significant separation (P < .01). Molecular interaction could be demonstrated between Pirh2 and p27^Kip1 in three HCC cell lines. In vitro, following release of two HCC cell lines from serum starvation, the expression of Pirh2 was upregulated, whereas p27^Kip1 was downregulated. Our results suggest that Pirh2 mediates the degradation of p27^Kip1 and participates in cell proliferation in human HCC. These findings provide a rational framework for further development of Pirh2 inhibitors as a novel class of anti-tumor agents.