title: Aberrant Expression of the Cell Polarity Regulator aPKCλ/ι is Associated With Disease Progression in Cervical Intraepithelial Neoplasia (CIN): A Possible Marker for Predicting CIN Prognosis.
abstract: Atypical protein kinase C λ/ι (aPKCλ/ι) is a regulator of epithelial cellular polarity. It is also overexpressed in several cancers and functions in cell proliferation and invasion. Therefore, we hypothesized that aPKCλ/ι may be involved in development and progression of cervical intraepithelial neoplasia (CIN), the precancerous disease of cervical cancer induced by human papillomavirus. To do this, we investigated the relationship between aPKCλ/ι expression and CIN. aPKCλ/ι expression level and subcellular localization were assessed in 192 CIN biopsy samples and 13 normal epithelial samples using immunohistochemistry. aPKCλ/ι overexpression (normal epithelium, 7.7%; CIN1, 41.7%; CIN2/3, 76.4%) and aPKCλ/ι nuclear localization (normal epithelium, 0.0%; CIN1, 36.9%; CIN2/3, 78.7%) were higher in CIN samples than normal samples (P<0.05), suggesting that CIN grade is related to aPKCλ/ι overexpression and nuclear localization. Then, 140 CIN cases were retrospectively analyzed for 4-yr cumulative disease progression and regression rates using the Cox proportional hazards model. CIN1 cases with aPKCλ/ι overexpression or aPKCλ/ι nuclear localization had a higher progression rate than CIN1 cases with normal aPKCλ/ι expression levels or cytoplasmic localization (62.5% vs. 9.7% and 63.1% vs. 9.4%, respectively; P<0.001). Multivariate analysis indicated that human papillomavirus types 16 and 18, aPKCλ/ι overexpression (hazard ratio=4.26; 95% confidence interval, 1.50-12.1; P=0.007), and aPKCλ/ι nuclear localization (hazard ratio=3.59; 95% confidence interval, 1.24-10.4; P=0.019) were independent risk factors for CIN1 progression. In conclusion, aPKCλ/ι could be useful for the therapeutic management of patients with CIN, particularly those with non-human papillomavirus 16/18 types.
authors.affiliation: Departments of Obstetrics and Gynecology and Molecular Reproductive Science (T.M., M.A.-S., R.A., A.T., F.H., E.M.) Molecular Biology (T.M., K.A., K.S., M.N., S.O.) Molecular Pathology (Y.N.) Biostatistics and Epidemiology (M.T.), Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan Department of Molecular Medical Science (K.A.), Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan Department of Surgical Pathology (Y.N.), Tokyo Women's Medical University Hospital, Shinjuku-ku, Tokyo, Japan Division of Carcinogenesis and Cancer Prevention (T.K.), National Cancer Center Research Institute, Cyuo-ku, Tokyo, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Mizushima
authors.forename: Mikiko
authors.initials: M
authors.lastname: Asai-Sato
authors.forename: Kazunori
authors.initials: K
authors.lastname: Akimoto
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Masataka
authors.initials: M
authors.lastname: Taguri
authors.forename: Kazunori
authors.initials: K
authors.lastname: Sasaki
authors.forename: Masa-aki
authors.initials: MA
authors.lastname: Nakaya
authors.forename: Ryoko
authors.initials: R
authors.lastname: Asano
authors.forename: Aya
authors.initials: A
authors.lastname: Tokinaga
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.forename: Fumiki
authors.initials: F
authors.lastname: Hirahara
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohno
authors.forename: Etsuko
authors.initials: E
authors.lastname: Miyagi
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis*; D018450:Disease Progression; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D030361:Papillomavirus Infections / Q000150:complications / Q000453:epidemiology; D011379:Prognosis; D011493:Protein Kinase C / Q000032:analysis / Q000096:biosynthesis*; D012189:Retrospective Studies; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000378:metabolism / Q000473:pathology* / Q000821:virology
chemical_list: D014408:Biomarkers, Tumor; C115015:PKC-3 protein; D011493:Protein Kinase C