FOXA2 Activates RND1 to Regulate Arachidonic Acid Metabolism Pathway and Suppress Cisplatin Resistance in Lung Squamous Cell Carcinoma

• Published in: The clinical respiratory journal 2024-08, Vol.18 (8), p.e13814-n/a
• Main Authors: Zhou, Yafu, Chen, Huiguo, Yan, Jianhua, Yao, Qi, Kong, Chunchu, Peng, You, Xiao, Shengying, Yang, Jinsong
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; arachidonic acid; Arachidonic Acid - metabolism; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cisplatin - pharmacology; Cisplatin - therapeutic use; DDP resistance; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; lung squamous cell carcinoma; Metabolism; Original; RND1; Squamous cell carcinoma
• ISSN: 1752-6981; 1752-699X; 1752-699X
• DOI: 10.1111/crj.13814

ABSTRACT Background The primary cause of cancer‐related fatalities globally is lung cancer. Although the chemotherapy drug cisplatin (DDP) has brought certain benefits to patients, the rapid development of drug resistance has greatly hindered treatment success. Methods We used the lung squamous cell carcinoma (LUSC) mRNA data set to explore the differentially expressed gene (RND1) in LUSC and detected RND1 expression in LUSC cells and DDP‐resistant cells by qRT‐PCR. Meanwhile, we performed abnormal expression treatment on RND1 and conducted CCK8, colony formation, and flow cytometry to evaluate the impact of RND1 expression on cell proliferation, apoptosis, and DDP resistance. In addition, we analyzed metabolism pathways involving RND1 using GSEA. We also used online tools such as hTFtarget and JASPAR to screen for the upstream transcription factor FOXA2 of RND1 and verified their relationship through CHIP and dual luciferase experiments. Finally, we validated the role of FOXA2‐RND1 in DDP resistance in LUSC through the above experiments. Results RND1 was downregulated in LUSC, and overexpression of RND1 repressed proliferation and DDP resistance of LUSC cells and facilitated cell apoptosis. RND1 modulated the arachidonic acid (AA) metabolism pathway, and FOXA2 positively manipulated RND1 expression. By activating FOXA2, stabilizing RND1, and regulating AA levels, the sensitivity of LUSC cells to DDP could be enhanced. Conclusion Our study suggested that FOXA2 positively modulated the RND1‐AA pathway, which repressed the resistance of LUSC cells to DDP. FOXA2 activates RND1 to suppress the arachidonic acid metabolism pathway and cisplatin resistance in lung squamous cell carcinoma.