He Fang, Ding Huan, Zhou Yang, Wang Yuanzhen, Xie Juan, Yang Shaoqi, Zhu Yongzhao
General Hospital of Ningxia Medical University, Yinchuan, China.
Graduate School, Ningxia Medical University, Yinchuan, China.
Front Med (Lausanne). 2022 Feb 1;8:792740. doi: 10.3389/fmed.2021.792740. eCollection 2021.
Aging acts as a dominating risk factor for human cancers. Herein, we systematically dissected the features of transcriptional aging-relevant genes in gastric cancer from multiple perspectives.
Based on the transcriptome profiling of prognostic aging-relevant genes, patients with gastric cancer in The Cancer Genome Atlas (TCGA) stomach adenocarcinoma (TCGA-STAD) cohort were clustered with a consensus clustering algorithm. Mutational landscape and chemotherapeutic responses were analyzed and immunological features (immunomodulators, immune checkpoint molecules, cancer immunity cycle, and tumor-infiltrating immune cells) were systematically evaluated across gastric cancer. Weighted gene co-expression network (WGCNA) was conducted for screening aging molecular phenotype-relevant genes, and key genes were identified with Molecular Complex Detection (MCODE) analyses. Expressions of key genes were examined in 20 paired tumors and controls with RT-qPCR and Western blotting. Proliferation and apoptosis were investigated in two gastric cancer cells under MYL9 deficiency.
Three aging-based molecular phenotypes (namely, C1, C2, and C3) were conducted in gastric cancer. Phenotype C1 presented the most prominent survival advantage and highest mutational frequencies. Phenotype C2 indicated low responses to sorafenib and gefitinib, while C3 indicated low responses to vinorelbine and gemcitabine. Additionally, phenotype C2 was characterized by enhanced immune and stromal activation and an inflamed tumor microenvironment. Seven aging molecular phenotype-relevant key genes (ACTA2, CALD1, LMOD1, MYH11, MYL9, MYLK, and TAGLN) were identified, which were specifically upregulated in tumors and in relation to dismal prognosis. Among them, MYL9 deficiency reduced proliferation and enhanced apoptosis in gastric cancer cells.
Collectively, aging-based molecular subtypes may offer more individualized therapy recommendations and prognosis assessment for patients in distinct subtypes.
衰老作为人类癌症的主要风险因素。在此，我们从多个角度系统剖析了胃癌中转录衰老相关基因的特征。
基于预后衰老相关基因的转录组分析，使用一致性聚类算法对癌症基因组图谱（TCGA）胃腺癌（TCGA-STAD）队列中的胃癌患者进行聚类。分析突变图谱和化疗反应，并系统评估胃癌中的免疫特征（免疫调节剂、免疫检查点分子、癌症免疫循环和肿瘤浸润免疫细胞）。进行加权基因共表达网络（WGCNA）以筛选衰老分子表型相关基因，并通过分子复合物检测（MCODE）分析鉴定关键基因。用RT-qPCR和蛋白质免疫印迹法检测20对肿瘤和对照中关键基因的表达。在MYL9缺陷的两种胃癌细胞中研究增殖和凋亡。
在胃癌中确定了三种基于衰老的分子表型（即C1、C2和C3）。表型C1具有最显著的生存优势和最高的突变频率。表型C2对索拉非尼和吉非替尼反应较低，而C3对长春瑞滨和吉西他滨反应较低。此外，表型C2的特征是免疫和基质激活增强以及肿瘤微环境炎症。鉴定出七个衰老分子表型相关关键基因（ACTA2、CALD1、LMOD1、MYH11、MYL9、MYLK和TAGLN），这些基因在肿瘤中特异性上调且与不良预后相关。其中，MYL9缺陷降低了胃癌细胞的增殖并增强了凋亡。
总体而言，基于衰老的分子亚型可为不同亚型的患者提供更个性化的治疗建议和预后评估。
