Institute of Human Respiratory Disease, Xinqiao Hospital, the Army Medical University (Third Military Medical University), Chongqing, China.
Department of Medical Biology, School of Basic Medical Science, Hubei University of Medicine, Shiyan, China.
Cell Prolif. 2020 Nov;53(11):e12924. doi: 10.1111/cpr.12924. Epub 2020 Oct 19.
Chemoresistance induced by cisplatin has become the major impediment to lung cancer chemotherapy. This study explored the potential chemoresistant genes and underlying mechanisms of chemoresistance in NSCLC.
Gene expression profile was integrated with DNA methylation profile to screen the candidate chemoresistant genes. Bioinformatic analysis and immunohistochemistry were used to analyse the association of a candidate gene with the characteristics of NSCLC patients. Recombinant lentivirus vectors were utilized to overexpress or silence candidate gene. Microarrays and immunoblotting were applied to explore the downstream targets of candidate gene. Xenograft models were established to validate the findings in vitro.
An increased ZNF300 expression was detected in three chemoresistant cell lines of NSCLC, and the higher expression of ZNF300 was associated with poor OS of NSCLC patients. Cells with upregulated ZNF300 presented chemoresistance and enhanced aggressive growth compared to cells with downregulated ZNF300. ZNF300 inhibited MAPK/ERK pathways and activated CDK1 through inhibiting WEE1 and MYT1 and modulating MYC/AURKA/BORA/PLK1 axis. ICA and ATRA improved the anti-tumour effect of cisplatin on chemoresistant cells by inducing differentiation.
ZNF300 promotes chemoresistance and aggressive behaviour of NSCLC through regulation of proliferation and differentiation by downregulating MAPK/ERK pathways and regulation of slow-cycling phenotype via activating CDK1 by inhibiting WEE1/MYT1 and modulating MYC/AURKA/BORA/PLK1 axis. Cisplatin, combined with ATRA and ICA, might be beneficial in chemoresistant cases of NSCLC.
顺铂诱导的化疗耐药已成为肺癌化疗的主要障碍。本研究旨在探讨非小细胞肺癌（NSCLC）化疗耐药的潜在耐药基因和机制。
整合基因表达谱和 DNA 甲基化谱筛选候选化疗耐药基因。采用生物信息学分析和免疫组织化学分析候选基因与 NSCLC 患者特征的相关性。利用重组慢病毒载体过表达或沉默候选基因。应用微阵列和免疫印迹技术探索候选基因的下游靶点。建立异种移植模型验证体外研究结果。
在三种 NSCLC 耐药细胞系中检测到 ZNF300 表达增加，且 ZNF300 表达越高，NSCLC 患者的总生存期越差。与下调 ZNF300 的细胞相比，上调 ZNF300 的细胞表现出耐药性，并增强了侵袭性生长。ZNF300 通过抑制 WEE1 和 MYT1 并调节 MYC/AURKA/BORA/PLK1 轴抑制 MAPK/ERK 通路，激活 CDK1。ICA 和 ATRA 通过诱导分化增强了顺铂对耐药细胞的抗肿瘤作用。
ZNF300 通过下调 MAPK/ERK 通路调节增殖和分化，通过抑制 WEE1/MYT1 并调节 MYC/AURKA/BORA/PLK1 轴激活 CDK1 促进非小细胞肺癌的化疗耐药和侵袭性行为。顺铂联合 ATRA 和 ICA 可能对化疗耐药的 NSCLC 有益。
