NEDD4 promotes cell growth and migration via PTEN/PI3K/AKT signaling in hepatocellular carcinoma

The novel E3 ubiquitin-protein ligase neural precursor cell-expressed developmentally downregulated protein 4 (NEDD4) has been implicated as a crucial factor promoting the tumorigenesis of several types of cancer. The present study investigated the oncogenic role of NEDD4 in hepatocellular carcinoma (HCC) by targeted small interfering RNA silencing of the tumor suppressor phosphatase and tensin homolog (PTEN). Using normal hepatocyte and HCC cell lines, the influence of NEDD4 depletion on proliferation and migration as well as on the PTEN/phosphatidylinositol-3-kinase/protein kinase B signaling pathway was assessed. Additionally, the expression of NEDD4 was assessed in HCC specimens from 78 patients. The in vitro immunohistochemistry results indicated that NEDD4 protein expression was higher, but PTEN expression was lower, in HCC cells compared with normal hepatocytes. The results from the MTT assay, wound healing experiment and Transwell assays demonstrated that NEDD4 depletion lead to decreased proliferation and migration ability of HCC cells. Results from western blotting and immunofluorescence demonstrated that silencing of NEDD4 disrupted the PTEN/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in HCC cells. A total of 55 (70.5%) of the HCC specimens stained positive for NEDD4 and expression significantly correlated with tumor size (P=0.047), differentiation degree (P=0.032), vascular invasion (P<0.001), and lymph node metastasis (P=0.005). Thus, NEDD4 appears to perform a critical role in promoting the proliferation and metastasis of HCC via activation of the PTEN/PI3K/AKT signaling pathway; as such, NEDD4 may be a promising target for novel treatments of HCC.