title: Expression of Pirh2, a p27(Kip1) ubiquitin ligase, in hepatocellular carcinoma: correlation with p27(Kip1) and cell proliferation.
abstract: 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.
authors.affiliation: Department of Pathology, Affiliated Cancer Hospital of Nantong University, Medical College of Nantong University, Nantong, P.R. China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Huang
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Qian
authors.forename: Chun
authors.initials: C
authors.lastname: Cheng
authors.forename: Song
authors.initials: S
authors.lastname: He
authors.forename: Linlin
authors.initials: L
authors.lastname: Sun
authors.forename: Qing
authors.initials: Q
authors.lastname: Ke
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Xia
authors.initials: X
authors.lastname: Pan
authors.forename: Fei
authors.initials: F
authors.lastname: He
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.forename: Runzhou
authors.initials: R
authors.lastname: Ni
authors.forename: Aiguo
authors.initials: A
authors.lastname: Shen
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*
chemical_list: D014408:Biomarkers, Tumor; C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C485369:RCHY1 protein, human; D044767:Ubiquitin-Protein Ligases