Huang Liang, Xu Zhenzhou, Xie Yu, Jiang Shusuan, Han Weiqing, Tang Zhengyan, Zhu Quan
Department of Urology, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, China.
Department of Urology, Xiangya Hospital, Central South University, Changsha, China.
Front Mol Biosci. 2022 Feb 21;9:803474. doi: 10.3389/fmolb.2022.803474. eCollection 2022.
Accumulated evidence demonstrates that ageing is a robust risk factor of prostate cancer prognosis. Herein, we conducted a systematic analysis about ageing-relevant molecules and relevant tumor microenvironment features in prostate cancer. Transcriptome data, clinical information, and mutational data of prostate cancer patients were retrospectively collected from the Cancer Genome Atlas cohort. In accordance with the expression of specific ageing-relevant genes, prostate cancer patients were clustered with consensus clustering analyses. WGCNA was adopted for determination of subtype-associated co-expression modules and genes. Thereafter, characteristic genes were further screened with random forest algorithm and a prognostic model was conducted with multivariate cox regression analyses. Tumor microenvironment-infiltrating immune cells were estimated with ssGSEA and ESTIMATE. Activities of the cancer immunity cycle and expressions of HLA and immune checkpoint molecules were then quantified across prostate cancer cases. A serious experiment was conducted to investigate the roles of EIF2S2 in prostate tumorigenesis. This study characterized three ageing-relevant subtypes (C1, C2, and C3) with diverse clinical prognosis. Subtype C1 presented the features of low mutational frequency and immune activation; C2 was characterized by stromal and immune activation; and C3 showed immune suppression. An ageing-derived gene signature was conducted, which independently and robustly predicted patients' prognosis. Additionally, this signature was in relation to immune inactivation. Among the genes in the signature, EIF2S2 triggered proliferation, invasion, and migration of LNCaP and PC-3 cells. Collectively, ageing-relevant molecular subtypes and gene signature might be of great significance to determine clinical outcomes and tumor microenvironment features and immunotherapeutic responses in prostate cancer.
越来越多的证据表明，衰老是前列腺癌预后的一个重要风险因素。在此，我们对前列腺癌中与衰老相关的分子和相关肿瘤微环境特征进行了系统分析。从癌症基因组图谱队列中回顾性收集前列腺癌患者的转录组数据、临床信息和突变数据。根据特定衰老相关基因的表达，通过一致性聚类分析对前列腺癌患者进行聚类。采用加权基因共表达网络分析（WGCNA）来确定亚型相关的共表达模块和基因。此后，使用随机森林算法进一步筛选特征基因，并通过多变量cox回归分析构建预后模型。用单样本基因集富集分析（ssGSEA）和ESTIMATE算法评估肿瘤微环境浸润免疫细胞。然后在前列腺癌病例中量化癌症免疫循环的活性以及人类白细胞抗原（HLA）和免疫检查点分子的表达。进行了一项严谨的实验来研究真核翻译起始因子2亚基2（EIF2S2）在前列腺肿瘤发生中的作用。本研究鉴定出三种与衰老相关的亚型（C1、C2和C3）具有不同的临床预后。C1亚型具有低突变频率和免疫激活的特征；C2亚型的特点是基质和免疫激活；C3亚型表现为免疫抑制。构建了一个源自衰老的基因特征，该特征能够独立且有力地预测患者的预后。此外，该特征与免疫失活有关。在该特征中的基因中，EIF2S2可促进LNCaP和PC - 3细胞的增殖、侵袭和迁移。总的来说，与衰老相关的分子亚型和基因特征对于确定前列腺癌的临床结局、肿瘤微环境特征和免疫治疗反应可能具有重要意义。
