Abstract
Small cell lung cancer (SCLC) accounts for approximately 15% of primary lung carcinomas and has the poorest outcome in all subtypes of lung cancer. The major hurdle for SCLC treatment failure is resistance to platinum-based chemotherapy. Therefore, an unmet need is to discover new targets that promote SCLC progression and chemoresistance. Based on the signature of ubiquitination-related genes (URGs), differentially expressed genes between cisplatin-resistant and cisplatin-sensitive SCLC cell lines were identified using the Genomics of Drug Sensitivity in Cancer (GDSC) database. The URGs associated with the prognosis were further screened by Cox and LASSO regression analyses, as well as a Kaplan-Meier survival analysis. The E3 ligase NEDD4 was identified to be associated with cisplatin resistance, poor prognosis and tumor metastasis in SCLC. The functional enrichment analysis indicated that the functions and pathways regulated by NEDD4 were enriched in cell proliferation, cell invasion, as well as ubiquitination and PI3K-AKT pathways in SCLC. The knockdown and overexpression of NEDD4 demonstrated that NEDD4 induced the phosphorylation of AKT in SCLC cells. Cell viability, wound healing and transwell invasion assays demonstrated that NEDD4 promoted the proliferation, chemoresistance and invasion of SCLC cells. These results suggest that NEDD4 is a biomarker of a poor prognosis for SCLC, and that it promotes AKT activation, SCLC progression and chemoresistance.
Keywords:
AKT; NEDD4; Small cell lung cancer; cell proliferation and invasion; chemoresistance.