Wang Shi-Shuo, Chen Gang, Li Sheng-Hua, Pang Jin-Shu, Cai Kai-Teng, Yan Hai-Biao, Huang Zhi-Guang, He Rong-Quan
Department of Pathology, The First Affilated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China.
Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China.
Onco Targets Ther. 2019 May 14;12:3695-3712. doi: 10.2147/OTT.S197676. eCollection 2019.
Autophagy is a major catabolic system by which eukaryotic cells undergo self-degradation of damaged, defective, or unwanted intracellular components. An abnormal autophagic level is implicated in the pathogenesis of multiple diseases, including cancers. The aim of this study is to explore the prognostic value of autophagy in bladder cancer (BC), which is a major cause of cancer-related death globally. First, 27 differentially expressed autophagy-related genes (ARGs) were identified in BC patients based on The Cancer Genome Atlas (TCGA) database. Functional enrichment analyses hinted that autophagy may act in a tumor-suppressive role in the initiation of BC. Then, the Cox proportional hazard regression model were employed to identify three key prognostic ARGs (JUN, MYC, and ITGA3), which were related with overall survival (OS) significantly in BC. The three genes represented important clinical significance and prognostic value in BC. Then a prognostic index (PI) was constructed. The PI was constructed based on the three genes, and significantly stratified BC patients into high- and low-risk groups in terms of OS (HR=1.610, 95% CI=1.200-2.160, =0.002). PI remained as an independent prognostic factor in multivariate analyses (HR=2.355, 95% CI=1.483-3.739, <0.001). When integrated with clinical characteristics of age and stage, an autophagy-clinical prognostic index (ACPI) was finally validated, which had improved performance in predicting OS of BC patients (HR=2.669, 95% CI=1.986-3.587, <0.001). The ACPI was confirmed in datasets of GSE13507 (HR=7.389, 95% CI=3.645-14.980, <0.001) and GSE31684 (HR=1.665, 95% CI=0.872-3.179, =0.122). This study provides a potential prognostic signature for predicting prognosis of BC patients and molecular insights of autophagy in BC.
自噬是一种主要的分解代谢系统，真核细胞通过该系统对受损、有缺陷或不需要的细胞内成分进行自我降解。自噬水平异常与包括癌症在内的多种疾病的发病机制有关。本研究的目的是探讨自噬在膀胱癌（BC）中的预后价值，膀胱癌是全球癌症相关死亡的主要原因。首先，基于癌症基因组图谱（TCGA）数据库，在BC患者中鉴定出27个差异表达的自噬相关基因（ARG）。功能富集分析表明，自噬在BC的起始阶段可能发挥肿瘤抑制作用。然后，采用Cox比例风险回归模型确定了三个关键的预后ARG（JUN、MYC和ITGA3），它们与BC患者的总生存期（OS）显著相关。这三个基因在BC中具有重要的临床意义和预后价值。然后构建了一个预后指数（PI）。该PI基于这三个基因构建，根据OS将BC患者显著分层为高风险和低风险组（HR = 1.610，95% CI = 1.200 - 2.160，P = 0.002）。在多变量分析中，PI仍然是一个独立的预后因素（HR = 2.355，95% CI = 1.483 - 3.739，P < 0.001）。当与年龄和分期的临床特征相结合时，最终验证了一个自噬 - 临床预后指数（ACPI），其在预测BC患者的OS方面具有更好的性能（HR = 2.669，95% CI = 1.986 - 3.587，P < 0.001）。在GSE13507数据集（HR = 7.389，95% CI = 3.645 - 14.980，P < 0.001）和GSE31684数据集（HR = 1.665，95% CI = 0.872 - 3.179，P = 0.122）中证实了ACPI。本研究为预测BC患者的预后提供了一个潜在的预后标志物，并为BC中自噬的分子机制提供了见解。
