Integrated analysis reveals critical cisplatin-resistance regulators E2F7 contributed to tumor progression and metastasis in lung adenocarcinoma

Xiaomin Mao; Shumin Xu; Huan Wang; Peng Xiao; Shumin Li; Jiaji Wu; Junhui Sun; Cheng Jin; Mo Shen; Yueli Shi; Bufu Tang; Ying Yang; Weiyu Chen; Zhiyong Xu; Yun Xu

doi:10.1186/s12935-024-03366-6

Integrated analysis reveals critical cisplatin-resistance regulators E2F7 contributed to tumor progression and metastasis in lung adenocarcinoma

Cancer Cell Int. 2024 May 17;24(1):173. doi: 10.1186/s12935-024-03366-6.

Authors

Xiaomin Mao^#¹, Shumin Xu^#², Huan Wang^#², Peng Xiao³, Shumin Li⁴, Jiaji Wu², Junhui Sun⁵, Cheng Jin⁶, Mo Shen², Yueli Shi², Bufu Tang³, Ying Yang², Weiyu Chen⁷, Zhiyong Xu⁸, Yun Xu⁹

Affiliations

¹ Department of Nursing, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Yiwu, 322000, China.
² Department of Respiratory and Critical Care Medicine, Center for Oncology Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
³ School of Medicine, Zhejiang University, Hangzhou, 310058, China.
⁴ Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
⁵ Department of Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
⁶ Wuxi Center for Disease Control and Prevention, The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi, 214023, China.
⁷ Department of Respiratory and Critical Care Medicine, Center for Oncology Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China. weiyuchen@zju.edu.cn.
⁸ Department of Respiratory and Critical Care Medicine, Center for Oncology Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China. xuzhiyong@zju.edu.cn.
⁹ Department of Respiratory and Critical Care Medicine, Center for Oncology Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China. 11618103@zju.edu.cn.

^# Contributed equally.

Abstract

Background: Drug resistance poses a significant challenge in cancer treatment, particularly as a leading cause of therapy failure. Cisplatin, the primary drug for lung adenocarcinoma (LUAD) chemotherapy, shows effective treatment outcomes. However, the development of resistance against cisplatin is a major obstacle. Therefore, identifying genes resistant to cisplatin and adopting personalized treatment could significantly improve patient outcomes.

Methods: By examining transcriptome data of cisplatin-resistant LUAD cells from the GEO database, 181 genes associated with cisplatin resistance were identified. Using univariate regression analysis, random forest and multivariate regression analyses, two prognostic genes, E2F7 and FAM83A, were identified. This study developed a prognostic model utilizing E2F7 and FAM83A as key indicators. The Cell Counting Kit 8 assay, Transwell assay, and flow cytometry were used to detect the effects of E2F7 on the proliferation, migration, invasiveness and apoptosis of A549/PC9 cells. Western blotting was used to determine the effect of E2F7 on AKT/mTOR signaling pathway.

Results: This study has pinpointed two crucial genes associated with cisplatin resistance, E2F7 and FAM83A, and developed a comprehensive model to assist in the diagnosis, prognosis, and evaluation of relapse risk in LUAD. Analysis revealed that patients at higher risk, according to these genetic markers, had elevated levels of immune checkpoints (PD-L1 and PD-L2). The prognostic and diagnosis values of E2F7 and FAM83A were further confirmed in clinical data. Furthermore, inhibiting E2F7 in lung cancer cells markedly reduced their proliferation, migration, invasion, and increased apoptosis. In vivo experiments corroborated these findings, showing reduced tumor growth and lung metastasis upon E2F7 suppression in lung cancer models.

Conclusion: Our study affirms the prognostic value of a model based on two DEGs, offering a reliable method for predicting the success of tumor immunotherapy in patients with LUAD. The diagnostic and predictive model based on these genes demonstrates excellent performance. In vitro, reducing E2F7 levels shows antitumor effects by blocking LUAD growth and progression. Further investigation into the molecular mechanisms has highlighted E2F7's effect on the AKT/mTOR signaling pathway, underscoring its therapeutic potential. In the era of personalized medicine, this DEG-based model promises to guide clinical practice.

Keywords: Cisplatin resistance; E2F7; Immune infiltration; Lung adenocarcinoma; Prognostic.