title: Diagnostic value of cyclin-dependent kinase/cyclin-dependent kinase inhibitor expression ratios as biomarkers of locoregional and hematogenous dissemination risks in oral squamous cell carcinoma.
abstract: The aim of the present study was to investigate the diagnostic value of cell cycle-related genes in oral squamous cell carcinoma (OSCC) by examining the expression of the following genes in 77 OSCC tissues by quantitative polymerase chain reaction: Cyclin genes (CCNA1,CCND1,CCND2andCCNE1), cyclin-dependent kinase (CDK) genes (CDK1,CDK2andCDK4), CDK inhibitor genes (CDKN2A,CDKN1A,CDKN1BandCDKN1C), and integrin and associated genes that we previously reported (ITGA3,ITGB4,CD9andJUP). The expression ratios of 66 combinations of the 11 cell cycle-related genes were analyzed to examine their associations with major clinical events using Mann-Whitney U and log-rank tests. Three expression ratios (CDK1/CDKN1B,CDK2/CDKN1AandCCNE1/CDK2) showed associations on univariate analyses and their diagnostic value was re-analyzed with integrin gene expression biomarkers (ITGA3/CD9andITGB4/JUP) using the Cox proportional hazards model and Kaplan-Meier estimates. Lymph node metastasis occurred in >90% of double-positive cases (high-ITGA3/CD9and high-CDK1/CDKN1B) irrespective of tumor size (P<0.0001). Primary site recurrence was found in >30% of double-positive cases (high-ITGA3/CD9and high-CDK2/CDKN1A) with tumors >20 mm (P=0.003). Triple-positive (high-ITGB4/JUP, high-ITGA3/CD9and high-CDK2/CDKN1A) was associated with distant metastasis (P<0.0001), but not with other clinical parameters. Disease-specific death occurred in 55% of double-positive cases (high-ITGA3/CD9and high-CDK2/CDKN1A) (P<0.0001) and a positive surgical margin was a significant factor for fatality in these cases. Reliable prediction of locoregional and hematogenous dissemination risks in OSCC using the four CDK and integrin gene expression ratios is a promising biomarker system. Clinical use of these parameters may improve the control rate with the use of new therapeutic strategies.
authors.affiliation: Division of Oral and Maxillofacial Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata 951-8514, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nagata
authors.affiliation: Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurita
authors.affiliation: Division of Oral and Maxillofacial Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata 951-8514, Japan.
authors.forename: Kohya
authors.initials: K
authors.lastname: Uematsu
authors.affiliation: Division of Oral and Maxillofacial Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata 951-8514, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kyoto University, Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan.
authors.forename: Katsu
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Division of Oral and Maxillofacial Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata 951-8514, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hoshina
authors.affiliation: Division of Oral and Maxillofacial Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata 951-8514, Japan.
authors.forename: Ritsuo
authors.initials: R
authors.lastname: Takagi
keywords: biomarker; cyclin-dependent kinase; cyclin-dependent kinase inhibitor; distant metastasis; integrin α3; integrin β4; lymph node metastasis; primary site recurrence; squamous cell carcinoma