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

Abstract

Abstract Backgrounds: Nei endonuclease VIII-like 3 (NEIL3), a novel tumor-related gene, was 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.Methods The expression pattern and prognostic value of NEIL3 in ccRCC patients were analyzed in multiple comprehensive databases and validated by qRT-PCR, western blotting analysis, immunohistochemistry, and tissue chips. The regulatory mechanisms were verified by the GSEA analysis, chromatin immunoprecipitation, dual-luciferase reporter gene, and immunofluorescence assay. The oncogenic effect of NEIL3 in ccRCC was confirmed by MTT assay, colony formation assay, tumorsphere assay, cell flow cytometry analysis, and xenograft tumor models.Results Nei endonuclease VIII-like 3 (NEIL3), a novel tumor-related gene, was highly expressed in ccRCC and positively correlated with adverse clinicopathological characteristics and worse prognosis. Mechanistically, we demonstrated that NEIL3 promoted cell proliferation and cell cycle progression in vitro and tumor growth in vivo. Furthermore, we found that NEIL3 overexpression activated the cyclin D1-Rb-E2F1 pathway. The E2F1 elevation then promoted the proliferation, cell cycle transition, and the NEIL3 expression, thus forming a feedback loop of the NEIL3-E2F1 axis to contribute to ccRCC progression. In addition, there was a positive correlation between NEIL3 and E2F1 expression in clinical specimens of ccRCC.Conclusion NEIL3 and cyclin D1-Rb-E2F1 pathway form a positive feedback loop and coordinately contribute to ccRCC progression. NEIL3 presents as a novel candidate for ccRCC diagnosis and treatment.