Oncogene Delta/Notch-Like EGF-Related Receptor Promotes Cell Proliferation, Invasion, and Migration in Hepatocellular Carcinoma and Predicts a Poor Prognosis.

PURPOSE:To determine the expression and function of Delta/Notch-like EGF-related receptor (DNER) in hepatocellular carcinoma (HCC). METHODS:The expression of DNER in 84 HCC tissue samples and matched adjacent noncancerous specimens, as well as HCC cells, were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Survival analysis was evaluated using Kaplan-Meier method. For experiments in vitro, cell viability was measured by Cell Counting Kit-8 Assay and Colony Formation Assay. Furthermore, cell invasion and migration assays were performed with Transwell Assay. RESULTS:The results showed that DNER was overexpressed in the tissues and cell lines of HCC (all, p < 0.05), and the upregulated expression of DNER was significantly correlated with advanced pathologic stage (p = 0.013) and pathologic-M1 (p = 0.012) in HCC patients. Survival analysis revealed that patients with high DNER levels had worse overall survival (OS) than those with low DNER levels (p = 0.004). More importantly, DNER could be an independent predictor of prognosis for OS (HR = 2.582, 95% CI 1.239-5.380, p = 0.011). In vitro, knockdown of DNER significantly suppressed cell proliferation, colony formation, cell invasion, and cell migration in HepG2 cells. Moreover, inhibition of DNER inactivated PI3K/AKT signaling pathway by downregulating the expression of p-PI3K, p-AKT, and p-70s6k. CONCLUSIONS:Taken together, DNER could promote proliferation, migration, and invasion of HCC cells by regulating the activation of PI3K/AKT pathway, and it might act as a potential prognostic biomarker for HCC.

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