ZNF300 Interacting with E2F3 Promoted the Malignant Progression of NSCLC by Regulating Proliferation, Differentiation, and Cell Cycle

Abstract

Background: Chemo-resistance induced by cisplatin (DDP) has become the major impediment to lung cancer chemotherapy. The study aimed to unearth an alternative route for reversing chemo-resistance and suppressing the malignant progression of tumors. Methods: Gene expression profile was integrated with DNA methylation profile of A549/DDP cells of human adenocarcinoma. Immunohistochemistry were used to analyze the association of gene with characteristics of NSCLC patients. Cell viability, apoptosis, cell cycle, migration, engulfment, and senescence were assessed between the different groups of cells. Genes related with differentiation and cell cycle, screened by microarrays, were examined by immunoblotting. Xenograft model was utilized to validate the results in vitro. Findings: ZNF300 was association with poor overall survival of NSCLC patients. Multidrug-resistant cells exhibited a more malignant behavior related to chemo-sensitive cells. Most of genes related with differentiation, cyclin-dependent kinase inhibitor, and MAPK/ERK pathways were downregulated, while most of genes related with cell cycle and cancer stem cell were upregulated in multidrug-resistant cells compared to chemo-sensitive cells. ICA improved the antitumor effect of cisplatin on multidrug-resistant cells. Interpretation: ZNF300 promoted the malignant behavior of multidrug-resistant cells through inhibiting differentiation via supressing MAPK/ERK pathways and enhancing cancer stem cell-like properties via upregulating Nanog and OCT4. Additionally, CDK1 activated by ZNF300 via inhibiting WEE1 and MYT1 and modulating AURKA/BORA/PLK1/CDC25 cascade promoted cells to enter cell cycle and escape the apoptosis caused by chemotherapeutic drug. ICA improved the antitumor effect of cisplatin on multidrug resistant cells by inducing differentiation. Funding Statement: This work was supported by the National Natural Scientific Fund of China (№:81372499), the Cultivating Project for Young Scholar at Hubei University of Medicine ( № :2018QDJZR01 and 2018QDJZR11), and the Open Project of Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine) (№:WDCM2018002). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The informed consents were obtained from all the patients undertaking surgery and participating in this study. All animal experiments were authorized by the Experimental Animal Ethics Committee of Xinqiao Hospital of the Army Medical University [SYXK(YU)2012-0011] and Hubei University of Medicine [SYXK(E)2016-0031].