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.

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

“…WWP2 overexpression was also associated with deregulated cell cycle via degradation of PTEN and activation of the PI3K/AKT signaling pathway. Silencing of WWP2 stabilized PTEN and inhibited growth of human tumor xenografts in nude mice [141]. Taken together, these findings suggest that WWP2 plays pro-oncogenic role through targeting tumor suppressor PTEN for degradation.…”

E3 Ubiquitin ligase RNF126 regulates the progression of tongue cancer

“…The tumorigenesis ability of E3 ubiquitin ligase is also emerging with defined biological activities. Several E3 ubiquitin ligase, including NEDD4 5, 10, ITCH 11, WWP2 12, 13, and FBXO32 6 have been confirmed to be related with the tumorigenesis. In order to find the tongue cancer‐related E3 ligases, we screened the human E3 ubiquitin ligase library and found the candidate molecule, RNF126.…”

Activin B Regulates Adhesion, Invasiveness, and Migratory Activities in Oral Cancer: a Potential Biomarker for Metastasis

“…mRNA and cDNA synthesis extractions were conducted as previously described 23 - 25 . Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed to evaluate target expression, the protocol of which was previously described 23 - 25 .…”

“…mRNA and cDNA synthesis extractions were conducted as previously described 23 - 25 . Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed to evaluate target expression, the protocol of which was previously described 23 - 25 . The primer sequences were as follows: inhibin beta b ( INHBB ), 5'-ATCAGCTTCGCCGAGACA-3' (forward) and 5'-GGTTGCCTTCGTTGGAGAT-3' (reverse); and glyceraldehyde-3-phosphate dehydrogenase ( GAPDH ), 5'-AACATCATCCCTGCCTCTACTGG-3' (forward) and 5'-TTGAAGTCAGAGGAGACCACTG-3' (reverse).…”