Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
PeerJ. 2023 Mar 10;11:e14996. doi: 10.7717/peerj.14996. eCollection 2023.
Lung adenocarcinoma is one of the most common tumors, and cisplatin is frequently used in treating lung adenocarcinoma patients. This study aimed to look into the roles and mechanisms of HNF4G in cisplatin resistance of lung adenocarcinoma.
MATERIALS & METHODS: Cisplatin resistance and gene expression data of 542 cell lines from the CTRP and CCLE databases were analyzed. HNF4G expression was detected in the lung adenocarcinoma cell lines after treatment with various concentrations of cisplatin. Cisplatin sensitivity curves were detected in cells that overexpressed or knocked down HNF4G. The ChIP-Seq data were then analyzed to identify the targets of HNF4G involved in cisplatin resistance. Expression and phosphorylation of the MAPK6/Akt pathway were detected after HNF4G was overexpressed or knocked down. Finally, ChIP-qPCR and dual-luciferase assays were used to investigate the regulation of HNF4G on MAPK6.
In cell lines, high expression of HNF4G was significantly positively correlated with cisplatin resistance, and lung adenocarcinoma patients who had high HNF4G expression had a poor prognosis. Cisplatin treatment increased HNF4G expression, and overexpression of HNF4G significantly increased the resistance to cisplatin in A549 and HCC827 cells, whereas knockdown of HNF4G had the opposite effect. HNF4G overexpression increased MAPK6 expression and activated the MAPK6/Akt pathway, while an Akt inhibitor reduced the effects of HNF4G on cisplatin resistance. HNF4G bound to the MAPK6 promoter region, promoting MAPK6 expression, according to ChIP-qPCR and luciferase assays.
By binding to the MAPK6 promoter region, HNF4G promotes MAPK6 expression and subsequent Akt phosphorylation, resulting in resistance to cisplatin in lung adenocarcinoma.
肺腺癌是最常见的肿瘤之一，顺铂常用于治疗肺腺癌患者。本研究旨在探讨 HNF4G 在肺腺癌顺铂耐药中的作用和机制。
分析了 CTRP 和 CCLE 数据库中 542 个细胞系的顺铂耐药和基因表达数据。用不同浓度的顺铂处理肺腺癌细胞系后，检测 HNF4G 的表达。在过表达或敲低 HNF4G 的细胞中检测顺铂敏感性曲线。然后分析 ChIP-Seq 数据，以确定涉及顺铂耐药的 HNF4G 靶标。过表达或敲低 HNF4G 后，检测 MAPK6/Akt 通路的表达和磷酸化。最后，使用 ChIP-qPCR 和双荧光素酶报告基因检测实验研究 HNF4G 对 MAPK6 的调控。
在细胞系中，HNF4G 高表达与顺铂耐药显著正相关，HNF4G 高表达的肺腺癌患者预后不良。顺铂处理增加了 HNF4G 的表达，过表达 HNF4G 显著增加了 A549 和 HCC827 细胞对顺铂的耐药性，而敲低 HNF4G 则产生相反的效果。HNF4G 过表达增加了 MAPK6 的表达并激活了 MAPK6/Akt 通路，而 Akt 抑制剂降低了 HNF4G 对顺铂耐药的影响。根据 ChIP-qPCR 和荧光素酶检测实验，HNF4G 结合到 MAPK6 启动子区域，促进 MAPK6 表达。
HNF4G 通过结合到 MAPK6 启动子区域，促进 MAPK6 表达和随后的 Akt 磷酸化，导致肺腺癌细胞对顺铂产生耐药性。
