Wu Lei, Quan Wen, Yue Guojun, Luo Qiong, Peng Dongxu, Pan Ying, Zhang Guihai
Department of Oncology, Zhuhai People's Hospital (Zhuhai Hospital affiliated with Jinan University), Zhuhai, Guangdong Province, P. R. China.
Zunyi Medical University, Zunyi, Guizhou Province, P. R. China.
BMC Cancer. 2021 Jan 5;21(1):15. doi: 10.1186/s12885-020-07725-0.
Autophagy is a highly conserved homeostatic process in the human body that is responsible for the elimination of aggregated proteins and damaged organelles. Several autophagy-related genes (ARGs) contribute to the process of tumorigenesis and metastasis of prostate cancer (PCa). Also, miRNAs have been proven to modulate autophagy by targeting some ARGs. However, their potential role in PCa still remains unclear.
An univariate Cox proportional regression model was used to identify 17 ARGs associated with the overall survival (OS) of PCa. Then, a multivariate Cox proportional regression model was used to construct a 6 autophagy-related prognostic genes signature. Patients were divided into low-risk group and high-risk group using the median risk score as a cutoff value. High-risk patients had shorter OS than low-risk patients. Furthermore, the signature was validated by ROC curves. Regarding mRNA and miRNA, 12 differentially expressed miRNAs (DEMs) and 1073 differentially expressed genes (DEGs) were detected via the GEO database. We found that miR-205, one of the DEMs, was negatively regulated the expression of ARG (NKX2-3). Based on STRING analysis results, we found that the NKX2-3 was moderately related to the part of genes among the 6 autophagy-related genes prognostic signature. Further, NKX 2-3 was significantly correlated with OS and some clinical parameters of PCa by cBioProtal. By gene set enrichment analysis (GSEA). Lastly, we demonstrated that the association between NKX2-3 and tumor mutation burden (TMB) and PDCD1 (programmed cell death 1) of PCa.
We identified that the six ARGs expression patterns are independent predictors of OS in PCa patients. Furthermore, our results suggest that ARGs and miRNAs are inter-related. MiR-205 was negatively regulated the expression of ARG (NKX2-3). Further analysis demonstrated that NKX2-3 may be a potential biomarker for predicting the efficacy of anti-PD-1 therapy in PCa.
The current study may offer a novel autophagy-related prognostic signature and may identify a promising miRNA-ARG pathway for predicting the efficacy of anti-PD-1 therapy in PCa.
自噬是人体中一种高度保守的稳态过程，负责清除聚集的蛋白质和受损的细胞器。几种自噬相关基因（ARGs）参与前列腺癌（PCa）的肿瘤发生和转移过程。此外，已有研究证明miRNA可通过靶向某些ARGs来调节自噬。然而，它们在PCa中的潜在作用仍不清楚。
使用单变量Cox比例回归模型来识别与PCa总生存期（OS）相关的17个ARGs。然后，使用多变量Cox比例回归模型构建一个6个自噬相关预后基因特征。以中位风险评分作为临界值，将患者分为低风险组和高风险组。高风险患者的OS比低风险患者短。此外，通过ROC曲线对该特征进行验证。关于mRNA和miRNA，通过GEO数据库检测到12个差异表达的miRNA（DEMs）和1073个差异表达基因（DEGs）。我们发现，DEM之一的miR-205对ARG（NKX2-3）的表达具有负调控作用。基于STRING分析结果，我们发现NKX2-3与6个自噬相关基因预后特征中的部分基因中度相关。此外，通过cBioProtal分析发现NKX 2-3与PCa的OS和一些临床参数显著相关。通过基因集富集分析（GSEA）。最后，我们证明了NKX2-3与PCa的肿瘤突变负荷（TMB）和程序性细胞死亡蛋白1（PDCD1）之间的关联。
我们确定这六个ARGs的表达模式是PCa患者OS的独立预测因子。此外，我们的结果表明ARGs和miRNA相互关联。MiR-205对ARG（NKX2-3）的表达具有负调控作用。进一步分析表明，NKX2-3可能是预测PCa抗PD-1治疗疗效的潜在生物标志物。
本研究可能提供一种新的自噬相关预后特征，并可能确定一条有前景的miRNA-ARG途径，用于预测PCa抗PD-1治疗的疗效。
