一种预测子宫内膜癌预后并与免疫浸润相关的新型坏死性凋亡相关miRNA特征。

A novel necroptosis-associated miRNA signature predicting prognosis of endometrial cancer and correlated with immune infiltration.

作者信息

Ye Zhongxue, Jiang Yafen, Wu Junlong

机构信息

Department of Gynecology, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China.

Department of Orthopedics, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China.

出版信息

Taiwan J Obstet Gynecol. 2023 Mar;62(2):291-298. doi: 10.1016/j.tjog.2022.09.009.

DOI:10.1016/j.tjog.2022.09.009

PMID:36965898

Abstract

OBJECTIVE

Necroptosis is a form of programmed cell death identified irrelevant to caspases, which plays an important role in the tumorigenesis and development of cancer. MicroRNAs (miRNAs) are important regulators of both necroptosis and cancer.

MATERIALS AND METHODS

Expression of sixteen necroptosis-associated miRNAs were analyzed in 546 endometrial cancer (EC) tissues and 33 paracancerous samples from the Cancer Genome Atlas (TCGA). Cox regression analysis was used to evaluate the correlations between miRNAs and overall survival. MiRNAs risk score (Mrs) and nomogram were established to assess the potential value of necroptosis-related miRNAs on prognosis. Expression of miRNA-148a-3p in endometrial cancer cells and endometrial epithelial cells was detected by quantitative real-time PCR (qRT-PCR). The targets genes of miR-148a-3p were predicted using miRDB, miRTarBase and TargetScan and the prognostic-related genes were screened. Immune infiltration analysis was conducted to explore the potential mechanism of these target genes.

RESULTS

We identified fourteen differentially expressed miRNAs and selected seven miRNAs (miR-15a-5p, miR148a-3p, miR-7-5p, miR-141-3p, miR-200a-5p, miR-223-3p, miR-16-5p) for prognostic-model construction. The area under the curve (AUC) of receiver operating characteristic (ROC) curve for 1-, 2- and 5-year survival were 0.678, 0.652 and 0.656 respectively. Multivariate analysis revealed that the Mrs was an independent prognostic factor considering other risk factors (HR = 1.928, 95% CI = 1.072-3.467, P = 0.028). Among these miRNAs, miRNA-148a-3p was up-regulated in cancer tissues and cells, and Kaplan-Meier analysis showed its significance in overall survival (OS). The target genes, DNAJB4 and PRNP, were associated with poor prognosis and correlated with tumor immune infiltration.

CONCLUSIONS

Our study constructed a novel necroptosis-associated miRNAs model for prognosis prediction, and DNAJB4 and PRNP may be therapeutic targets for EC.

摘要

目的

坏死性凋亡是一种与半胱天冬酶无关的程序性细胞死亡形式，在癌症的发生和发展中起重要作用。微小RNA（miRNA）是坏死性凋亡和癌症的重要调节因子。

材料与方法

对来自癌症基因组图谱（TCGA）的546例子宫内膜癌（EC）组织和33例癌旁样本中16种与坏死性凋亡相关的miRNA的表达进行分析。采用Cox回归分析评估miRNA与总生存期之间的相关性。建立miRNA风险评分（Mrs）和列线图，以评估坏死性凋亡相关miRNA对预后的潜在价值。通过定量实时PCR（qRT-PCR）检测miRNA-148a-3p在子宫内膜癌细胞和子宫内膜上皮细胞中的表达。使用miRDB、miRTarBase和TargetScan预测miR-148a-3p的靶基因，并筛选与预后相关的基因。进行免疫浸润分析以探讨这些靶基因的潜在机制。

结果

我们鉴定出14种差异表达的miRNA，并选择7种miRNA（miR-15a-5p、miR148a-3p、miR-7-5p、miR-141-3p、miR-200a-5p、miR-223-3p、miR-16-5p）用于构建预后模型。1年、2年和5年生存率的受试者工作特征（ROC）曲线下面积（AUC）分别为0.678、0.652和0.656。多变量分析显示，考虑到其他风险因素，Mrs是一个独立的预后因素（HR = 1.928，95%CI = 1.072 - 3.467，P = 0.028）。在这些miRNA中，miRNA-148a-3p在癌组织和细胞中上调，Kaplan-Meier分析显示其在总生存期（OS）中具有显著性。靶基因DNAJB4和PRNP与预后不良相关，并与肿瘤免疫浸润相关。