title: Cavin-2 in oral cancer: A potential predictor for tumor progression.
abstract: Cavin-2 (CVN2) affects formation of large caveolae, which are membrane-rich cholesterol domains associated with several functions in signal transduction. Accumulating evidence suggests that CVN2 is present in many cellular types; however, the molecular mechanisms of CVN2 in cancers and its clinical relevance are unknown. We proposed a mechanism by which CVN2 regulates caveolin-1 expression leading to slow cellular proliferation by inactivation of the extracellular regulated kinase (ERK) pathway. Quantitative reverse transcriptase-polymerase chain reaction and immunoblot analyses were used to assess the CVN2 regulation mechanism in oral squamous cell carcinoma (OSCC). Immunohistochemistry (IHC) was performed to analyze the correlation between CVN2 expression and clinical behavior in 115 patients with OSCC. A CVN2 overexpressed model of OSCC cells (oeCVN2 cells) was used for functional experiments. CVN2 expression was down-regulated significantly (P < 0.05) in OSCCs compared with normal counterparts in vitro and in vivo. In addition to the findings that a serum deprivation culture induced up-regulation of CVN2 and slowed cellular proliferation, oeCVN2 cell growth decreased because of cell-cycle arrest at the G1 phase resulting from up-regulated cyclin-dependent kinase inhibitors (p21(Cip1) and p27(Kip1) ) and down-regulated cyclins (cyclin D1, cyclin E) and cyclin-dependent kinases (CDK2, CDK4, and CDK6). Interestingly, CVN2 overexpression facilitated caveolin-1 recruitment and colocalization with each other. We also found decreased ERK phosphorylation levels, an upstream event in cell-cycle arrest. Clinically, IHC data from primary OSCCs showed high tumoral progression in CVN2-negative patients with OSCC. CVN2 may be a possible key regulator of OSCC progression via the CVN2/caveolin-1/ERK pathway and a potential therapeutic target for developing new treatments for OSCCs. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: Motoharu
authors.initials: M
authors.lastname: Unozawa
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chuo-ku, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasamatsu
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chuo-ku, Chiba, Japan.
authors.forename: Morihiro
authors.initials: M
authors.lastname: Higo
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: Chonji
authors.initials: C
authors.lastname: Fukumoto
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Koyama
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sakazume
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chuo-ku, Chiba, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Nakashima
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chuo-ku, Chiba, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ogawara
authors.affiliation: Department of Oral and Maxillofacial Surgery Research Institute, National Defense Medical College Hospital, Tokorozawa, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yokoe
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chuo-ku, Chiba, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiiba
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan.|Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chuo-ku, Chiba, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tanzawa
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan.|Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chuo-ku, Chiba, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Uzawa
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D028044:Phosphate-Binding Proteins; D010766:Phosphorylation
chemical_list: C495540:CAV1 protein, human; C112303:CAVIN2 protein, human; D002352:Carrier Proteins; D051242:Caveolin 1; D028044:Phosphate-Binding Proteins
keywords: caveolin-1; cavin-2; oral squamous cell carcinoma; tumoral progression