title: WWP2 is overexpressed in human oral cancer, determining tumor size and poor prognosis in patients: downregulation of WWP2 inhibits the AKT signaling and tumor growth in mice.
abstract: The WW domain containing E3 ubiquitin protein ligase 2 (WWP2) encodes a member of the Nedd4 family of E3 ligases, which catalyzes the final step of the ubiquitination cascade. WWP2 is involved in tumoral growth with degradation of the tumor suppressor phosphatase and tensin homologue deleted on chromosome TEN (PTEN). However, little is known about the mechanisms and roles of WWP2 in human malignancies including oral squamous cell carcinomas (OSCCs). We found frequent WWP2 overexpression in all OSCC-derived cell lines examined that was associated with cellular growth by accelerating the cell cycle in the G1 phase via degradation of PTEN and activation of the PI3K/AKT signaling pathway. Our in vivo data of WWP2 silencing showed dramatic inhibition of tumoral growth with increased expression of PTEN. Our 104 primary OSCCs had significantly higher expression of WWP2 than their normal counterparts. Moreover, among the clinical variables analyzed, enhanced WWP2 expression was correlated with primary tumoral size and poor prognosis. These data suggested that WWP2 overexpression contributes to neoplastic promotion via the PTEN/PI3K/AKT pathway in OSCCs. WWP2 is likely to be a biomarker of tumoral progression and prognosis and a potential therapeutic target for development of anticancer drugs in OSCCs.
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Inohana, 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, Inohana, 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, Inohana, Chuo-ku, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasamatsu
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan.
authors.forename: Motoharu
authors.initials: M
authors.lastname: Unozawa
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Shida-Sakazume
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Inohana, Chuo-ku, Chiba, Japan.
authors.forename: Morihiro
authors.initials: M
authors.lastname: Higo
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Inohana, 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 Medical Oncology, Graduate School of Medicine, Chiba University, Inohana, 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, Inohana, Chuo-ku, Chiba, Japan ; Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Inohana, 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, Inohana, Chuo-ku, Chiba, Japan ; Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Inohana, Chuo-ku, Chiba, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Uzawa
keywords: PTEN/PI3K/AKT pathway; WWP2; cell cycle; oral squamous carcinoma; tumoral growth