Department of General Surgery, Shanghai Fengxian Central Hospital (Affiliated Fengxian Hospital to Southern Medical University), The Third School of Clinical Medicine, Southern Medical University, Shanghai, China.
The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.
J Cell Biochem. 2020 Feb;121(2):1317-1331. doi: 10.1002/jcb.29368. Epub 2019 Sep 4.
Circular RNAs (circRNAs) can interact with microRNAs (miRNAs) to regulate gene expression in cancer cells. However, the roles of competitive endogenous RNA (ceRNA) networks consisting of differentially expressed circRNAs (DECs), miRNAs, and messenger RNAs (mRNAs) in stomach adenocarcinoma (STAD) remain unclear. This study was performed to explore novel regulatory networks in STAD.
The circRNA expression profiles, as well as miRNA and mRNA sequence data of STAD, were retrieved from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), respectively. Candidates were identified to construct a network through a comprehensive bioinformatics strategy. The expression of hub-genes identified by protein-protein interactions (PPI) was validated by quantitative reverse transcription (RT) polymerase chain reaction.
A total of 51 DECs were identified in the GSE83521 and GSE89143 datasets of GEO. A total of 11 448 differentially expressed mRNAs (DEMs) and 458 differentially expressed miRNAs (DEMIs) were obtained by RNA sequencing of TCGA-STAD. Prediction by using five online databases (Cancer-Specific CircRNA, CircInteractome, miRTarBase, miRDB, and TargetScan) resulted in the selection of 6 DECs, 6 DEMIs, and 36 DEMs to establish a circRNA-miRNA-mRNA regulatory network based on the interactions of circRNA-miRNA and miRNA-mRNA. Through PPI analysis, four hub-genes (COL10A1, COL5A2, COL4A1, and COL3A1) were discovered. Moreover, overexpressions of COL10A1, COL5A1, and COL4A1 were associated with a poor overall survival rate of patients with STAD. On the basis of TNM staging, we found that the expressions of COL10A1, COL5A2, and COL3A1 in T2, T3, and T4 was significantly higher than in T1. Hub-genes expressions were validated in STAD tissues and cell lines.
Our study provides a novel perspective on the regulatory mechanism of STAD involving ceRNAs including DECs, DEMIs, and DEMs.
环状 RNA（circRNAs）可以与 microRNAs（miRNAs）相互作用，从而调节癌细胞中的基因表达。然而，由差异表达的环状 RNA（DECs）、miRNAs 和信使 RNA（mRNAs）组成的竞争性内源 RNA（ceRNA）网络在胃腺癌（STAD）中的作用尚不清楚。本研究旨在探索 STAD 中的新型调控网络。
从基因表达综合数据库（GEO）和癌症基因组图谱（TCGA）分别检索 STAD 的 circRNA 表达谱以及 miRNA 和 mRNA 序列数据。通过全面的生物信息学策略确定候选物，以构建网络。通过蛋白质-蛋白质相互作用（PPI）鉴定的枢纽基因的表达通过定量逆转录（RT）聚合酶链反应进行验证。
从 GEO 的 GSE83521 和 GSE89143 数据集中共鉴定出 51 个 DECs。通过 TCGA-STAD 的 RNA 测序获得了 11448 个差异表达的 mRNAs（DEMs）和 458 个差异表达的 miRNAs（DEMIs）。通过五个在线数据库（癌症特异性 circRNA、CircInteractome、miRTarBase、miRDB 和 TargetScan）的预测，选择了 6 个 DECs、6 个 DEMIs 和 36 个 DEMs，以基于 circRNA-miRNA 和 miRNA-mRNA 的相互作用建立 circRNA-miRNA-mRNA 调控网络。通过 PPI 分析，发现了四个枢纽基因（COL10A1、COL5A2、COL4A1 和 COL3A1）。此外，COL10A1、COL5A1 和 COL4A1 的过表达与 STAD 患者的总生存率降低有关。基于 TNM 分期，我们发现 COL10A1、COL5A2 和 COL3A1 在 T2、T3 和 T4 中的表达明显高于 T1。在 STAD 组织和细胞系中验证了枢纽基因的表达。
本研究提供了一个新的视角，即包括 DECs、DEMIs 和 DEMs 在内的 ceRNAs 参与了 STAD 的调控机制。
