Guo Di, Feng Yonghai, Liu Peijie, Yang Shanshan, Zhao Wenfei, Li Hongyun
Department of Respiratory and Critical Care Medicine, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
Oncol Lett. 2024 Feb 29;27(4):186. doi: 10.3892/ol.2024.14320. eCollection 2024 Apr.
Ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, is implicated in the development and therapeutic responses of cancer. However, the role of ferroptosis-related gene profiles in lung squamous cell carcinoma (LSCC) remains largely unknown. The present study aimed to identify the prognostic roles of ferroptosis-related genes in LSCC. Sequencing data from the Cancer Genome Atlas were analyzed and ferroptosis-related gene expression between tumor and para-tumor tissue was identified. The prognostic role of these genes was also assessed using Kaplan-Meier analyses and univariate and multivariate Cox proportional hazards regression model analyses. Immunological correlation, tumor stemness, drug sensitivity and the transcriptional differences of heat shock protein (HSP)A5 in LSCC were also analyzed. Thereafter, the expression of HSPA5 in 100 patients with metastatic LSCC was evaluated using immunohistochemistry (IHC) and the clinical significance of these markers with different risk factors was assessed. Of the 22 ferroptosis-related genes, the expression of HSPA5, HSPB1, glutathione peroxidase 4, Fanconi anemia complementation group D2, CDGSH iron sulfur domain 1, farnesyl-diphosphate farnesyltransferase 1, nuclear factor erythroid 2 like 2, solute carrier (SLC)1A5, ribosomal protein L8, nuclear receptor coactivator 4, transferrin receptor and SLC7A11 was significantly increased in LSCC compared with adjacent tissues. However, only high expression of HSPA5 was able to predict progression-free survival (PFS) and disease-free survival in LSCC. Although HSPA5 was also significantly elevated in patients with lung adenocarcinoma, HSPA5 expression did not predict the prognosis of patients with lung adenocarcinoma. Of note, a higher expression of HSPA5 was related to higher responses to chemotherapy but not to immunotherapy. In addition, HSPA5 expression was positively correlated with 'ferroptosis', 'cellular responses to hypoxia', 'tumor proliferation signature', 'G2M checkpoint', 'MYC targets' and 'TGFB'. IHC analysis also demonstrated that a high expression of HSPA5 in patients with metastatic LSCC in the study cohort was associated with shorter PFS and overall survival. In conclusion, the present study demonstrated that the expression of the ferroptosis-related gene HSPA5 may be a negative prognostic marker for LSCC.
铁死亡是一种由过度脂质过氧化驱动的铁依赖性调节性细胞死亡形式，与癌症的发生发展及治疗反应有关。然而，铁死亡相关基因谱在肺鳞状细胞癌（LSCC）中的作用仍 largely unknown。本研究旨在确定铁死亡相关基因在LSCC中的预后作用。分析了来自癌症基因组图谱的测序数据，确定了肿瘤组织与癌旁组织之间铁死亡相关基因的表达。还使用Kaplan-Meier分析以及单变量和多变量Cox比例风险回归模型分析评估了这些基因的预后作用。还分析了LSCC中的免疫相关性、肿瘤干性、药物敏感性以及热休克蛋白（HSP）A5的转录差异。此后，使用免疫组织化学（IHC）评估了100例转移性LSCC患者中HSPA5的表达，并评估了这些标志物与不同危险因素的临床意义。在22个铁死亡相关基因中，与相邻组织相比，HSPA5、HSPB1、谷胱甘肽过氧化物酶4、范可尼贫血互补组D2、CDGSH铁硫结构域1、法尼基二磷酸法尼基转移酶1、核因子红细胞2样2、溶质载体（SLC）1A5、核糖体蛋白L8、核受体辅激活因子4、转铁蛋白受体和SLC7A11在LSCC中的表达显著增加。然而，只有HSPA5的高表达能够预测LSCC的无进展生存期（PFS）和无病生存期。尽管HSPA5在肺腺癌患者中也显著升高，但HSPA5表达并不能预测肺腺癌患者的预后。值得注意的是，HSPA5的较高表达与对化疗的较高反应相关，但与免疫治疗无关。此外，HSPA5表达与“铁死亡”、“细胞对缺氧的反应”、“肿瘤增殖特征”、“G2M检查点”、“MYC靶点”和“转化生长因子β”呈正相关。IHC分析还表明，研究队列中转移性LSCC患者中HSPA5的高表达与较短的PFS和总生存期相关。总之，本研究表明，铁死亡相关基因HSPA5的表达可能是LSCC的一个不良预后标志物。
