NEIL3 promotes cell proliferation of ccRCC via the cyclin D1-Rb-E2F1 feedback loop regulation

Nei endonuclease VIII-like 3 (NEIL3), a novel tumor-related gene, is differentially expressed and involved in pathophysiological processes in multiple tumors. However, the potential biological functions and molecular mechanisms of NEIL3 in human clear cell renal cell carcinoma (ccRCC) have not been identified. In this research, we demonstrated that NEIL3, transcriptionally activated by E2F1, served as an oncogene to facilitate cell proliferation and cell cycle progression and contribute to tumorigenesis via the cyclin D1-Rb-E2F1 feedback loop in ccRCC. First, we found that NEIL3 expression was upregulated in ccRCC tissues and cell lines compared with matched adjacent nontumor tissues and renal tubular epithelial cells and was also positively correlated with adverse clinicopathological characteristics, such as advanced cancer stages and higher tumor grades, and acted as an independent prognostic marker in ccRCC. Mechanistically, we demonstrated that NEIL3 promoted cell proliferation, DNA replication and cell cycle progression in vitro and tumor growth in vivo. Furthermore, we found that NEIL3 overexpression activated the cyclin D1-Rb-E2F1 pathway, and the E2F1 upregulation transcriptionally activated NEIL3 expression, thus forming a feedback loop. In addition, there was a positive correlation between NEIL3 and E2F1 expression in clinical specimens of ccRCC. Taken together, our results suggest that NEIL3 serves as a proto-oncogene in ccRCC and presents as a novel candidate for ccRCC diagnosis and treatment.