title: High expression of Pirh2, an E3 ligase for p27,  is associated with low expression of p27 and poor  prognosis in head and neck cancers.
abstract: Downregulation of the cyclin-dependent kinase inhibitory protein p27 is frequently observed in various cancers due to enhancement of its degradation. We recently reported that p53-inducible protein with RING-H2 domain (Pirh2) is a novel ubiquitin ligase for p27, required for the ubiquitylation and consequent degradation of p27 protein. However, there is no reports about the involvement of Pirh2 in both p27 downregulation and pathogenesis in human cancers. In the present study, we investigated them using cultured cell lines and surgical specimens derived from human head and neck squamous cell carcinoma (HNSCC). Depletion of Pirh2 by short interfering RNA induced accumulation of p27 and inhibited the growth of cultured HNSCC cells. By immunohistochemical analysis in 57 cases of HNSCC specimens, higher levels of Pirh2 expression (labeling index > or = 60%) were found in 61.4% of HNSCC in comparison with 0% of normal mucosa. In addition, 83.3% of HNSCC with lower p27 expression (labeling index < 20%) displayed high Pirh2 levels. Therefore, Pirh2 expression was inversely correlated with p27 expression. Finally, Pirh2 expression was well correlated with poor prognosis. These findings suggest that Pirh2 overexpression may have an important role in the development and maintenance of HNSCC at least partially through p27 degradation, and that Pirh2 may be a potential molecular target for human HNSCC.
authors.affiliation: Department of Biochemistry 1, Hamamatsu University School of Medicine, Higashi-ku, Hamamatsu, Shizuoka, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Shimada
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Yoh
authors.initials: Y
authors.lastname: Dobashi
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Isobe
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hattori
authors.forename: Chiharu
authors.initials: C
authors.lastname: Uchida
authors.forename: Kenji
authors.initials: K
authors.lastname: Abe
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Kotake
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Oda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kitagawa
mesh_terms: D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D011379:Prognosis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27; C485369:RCHY1 protein, human; D044767:Ubiquitin-Protein Ligases