Abstract
Accumulating evidence has demonstrated that circular RNAs (circRNAs) play vital roles in cancer progression. However, the underlying molecular mechanisms of circRNAs remain poorly elucidated in gastric cancer (GC). The main purpose of present study is to explore the underlying regulatory mechanism by constructing a circRNA-associated competitive endogenous RNA (ceRNA) network and further establish a robust prognostic signature for patients with GC. Based on expression data of circRNA, microRNA, and mRNA derived from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, a circRNA-associated ceRNA network, containing 15 cirRNAs, 9 microRNAs, and 35 mRNAs, was constructed using the Starbase database. Functional enrichment analysis showed that the ceRNA network might be involved in many cancer-related pathways, such as regulation of transcription from RNA polymerase II promoter, mesodermal cell differentiation, and focal adhesion. A protein-protein interaction network was constructed based on genes within the circRNA-associated ceRNA network. We found that six of ten hub genes within the PPI network were significantly associated with overall survival (OS). Thus, using the LASSO method, we constructed a three-gene prognostic signature based on TCGA-GC cohort, which could classify GC patients into low-risk and high-risk groups with significant difference in OS (HR = 1.9, 95%CI = 1.14‐3.2, and log-rank p = 0.001). The prognostic performance of the three-gene signature was verified in GSE15459 (HR = 1.9, 95%CI = 1.27‐3.0, and log − rank p = 2.2E − 05) and GSE84437 (HR = 1.5, 95%CI = 1.17‐2.0, and log − rank p = 6.3E − 04). Multivariate Cox analysis further revealed that the three-gene prognostic signature could serve as an independent risk factor for OS. Taken together, our findings contribute to a better understanding of the underlying mechanisms of circRNAs in GC progression. Furthermore, a robust prognostic signature is meaningful to facilitate individualized treatment for patients with GC.
Highlights
Gastric cancer (GC) has been well known as one of the most malignant tumors with high incidence and mortality worldwide, which is responsible for over 1,000,000 new cases and 780,000 deaths predicted each year, making it ranks the fifth most frequently diagnosed cancer and the third leading cause of cancer-related death [1]
This study provided a valuable insight for elucidating the regulatory mechanisms of circRNAs and constructing a reliable prognostic signature, which could guide individualized therapies and improve the clinical outcome for GC patients
To summarize, based on the expression data of circRNAs, miRNAs, and mRNAs, we developed a circRNA-associated competitive endogenous RNA (ceRNA) network to investigate the underlying regulatory mechanism in GC
Summary
Gastric cancer (GC) has been well known as one of the most malignant tumors with high incidence and mortality worldwide, which is responsible for over 1,000,000 new cases and 780,000 deaths predicted each year, making it ranks the fifth most frequently diagnosed cancer and the third leading cause of cancer-related death [1]. In the last few years, along with an extensive characterization of the protein-coding genome in gastric cancer, BioMed Research International increasing attention has been focused on circular RNAs (circRNAs), which are a class of endogenous noncoding RNAs characterized by covalently closed loop structures. Accumulating evidence has demonstrated that the dysregulation of circRNAs could play critical roles in the initiation and progression of cancer [9, 10]. Hsiao et al reported that circCCDC66 was upregulated in all stages of colon cancer and negatively correlated with prognosis, highlighting a novel oncogenic function in cancer progression and metastasis [11]. The research performed by Yao et al demonstrated that circRNA_100876 expression was significantly elevated in non-small-cell lung cancer tissues and was closely associated with lymph node metastasis and tumor-node-metastasis stage, indicating that circRNA_100876 may be a potential cancer marker of patients with non-small-cell lung cancer [12]. The biological function and regulatory mechanism of circRNAs in GC remain poorly elucidated and require further investigation
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