构建基于 circRNA 的 ceRNA 网络,揭示 circRNAs 在转移性透明细胞肾细胞癌进展和预后中的作用。

Construction of circRNA-based ceRNA network to reveal the role of circRNAs in the progression and prognosis of metastatic clear cell renal cell carcinoma.

机构信息

The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.

First Clinical Medical College of Nanjing Medical University, Nanjing 210029, China.

出版信息

Aging (Albany NY). 2020 Nov 20;12(23):24184-24207. doi: 10.18632/aging.104107.

Abstract

CircRNAs are now under hot discussion as novel promising bio-markers for patients with clear cell renal cell carcinoma. The purpose of our study is to identify several circRNAs related to the metastasis and progression of clear cell renal cell carcinoma, and to further investigate the mechanism of their influence on tumor progression. The transcriptome data of ccRCC and clinical characteristics used in this study were downloaded from the The Cancer Genome Atlas and Gene Expression Omnibus database. A total of 114 circRNAs were found to be related to tumor initiation, progression and metastasis after the intersection. In addition, 14 miRNAs and 201 eligible mRNAs were selected as targets gene, respectively. CeRNA network was constructed based on 8 circRNAs, 14 miRNAs, and 201 mRNAs. Besides, another 6 hub genes were identified via the PPI network. It should be noted that only TRIM2 was confirmed as an independent prognostic factor, which was simultaneously significantly related to both clinical stage and pathological grade in clinical cohorts. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis indicated the possible function of TRIM2 in ccRCC progression, such as ubiquitin mediated protein hydrolysis, cell adhesion molecules, Th17 cell differentiation signaling pathway and so on. Gene set enrichment analysis analysis revealed that TRIM2 may be involved in ubiquitin mediated proteolysis, apoptosis, autophagy and citrate cycle TCA cycle. Hub circ_RNAs expressions were validated in ccRCC tissues and cell lines. Our study revealed that the hsa_circ_0002286 / has-mir-222-5p / TRIM2 axis played a critical role in the progression of ccRCC. Specifically, it may inhibit the metastasis and progression of ccRCC, which could serve as a potential therapeutic target.

摘要

CircRNAs 作为透明细胞肾细胞癌患者新的有前途的生物标志物,正受到热议。本研究旨在鉴定几种与透明细胞肾细胞癌转移和进展相关的 circRNAs,并进一步研究其影响肿瘤进展的机制。本研究使用的透明细胞肾细胞癌的转录组数据和临床特征从癌症基因组图谱和基因表达综合数据库中下载。经过交叉验证,共发现 114 个 circRNAs 与肿瘤起始、进展和转移有关。此外,分别选择了 14 个 miRNA 和 201 个合格的 mRNAs 作为靶基因。基于 8 个 circRNAs、14 个 miRNA 和 201 个 mRNAs 构建了 CeRNA 网络。另外,通过 PPI 网络还鉴定了另外 6 个 hub 基因。需要注意的是,只有 TRIM2 被证实是一个独立的预后因素,在临床队列中同时与临床分期和病理分级显著相关。京都基因与基因组百科全书和基因本体论分析表明,TRIM2 在透明细胞肾细胞癌进展中的可能作用,如泛素介导的蛋白水解、细胞黏附分子、Th17 细胞分化信号通路等。基因集富集分析表明,TRIM2 可能参与泛素介导的蛋白水解、细胞凋亡、自噬和柠檬酸循环 TCA 循环。hub circ_RNAs 在透明细胞肾细胞癌组织和细胞系中的表达得到验证。本研究揭示了 hsa_circ_0002286/has-mir-222-5p/TRIM2 轴在透明细胞肾细胞癌进展中起着关键作用。具体来说,它可能抑制透明细胞肾细胞癌的转移和进展,可作为潜在的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d3/7762515/69fc97707eb8/aging-12-104107-g001.jpg

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