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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.
Highlights
Considerable evidence has suggested that unexpected increases in cellular proliferation occur due to disruption of the cell-cycle control
These analyses indicated that both transcription and translational products of www.impactjournals.com/oncoscience protein ligase 2 (WWP2) were highly expressed in oral squamous cell carcinomas (OSCCs)-derived cell lines
WWP2 is a member of the Nedd4 family of E3 ligases, which catalyzes the final step of the ubiquitination cascade[14,15,16,17,18,19]
Summary
Considerable evidence has suggested that unexpected increases in cellular proliferation occur due to disruption of the cell-cycle control. The precise mechanism and clinical benefit of cell-cycle regulation in OSCCs has not been determined. The ubiquitin-proteasome pathway is a principal protein-homeostasis mechanism that controls protein quality [8,9,10,11]. A well-studied function of ubiquitination is its role in protein degradation by which polyubiquitinated proteins are recognized by proteasome and degraded rapidly. There is increasing evidence that aberrant expression of the enzymes involved in regulation of the ubiquitination process plays an important role in malignant transformation [12, 13]
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