Comprehensive In Silico Analysis of a Novel Serum Exosome-Derived Competitive Endogenous RNA Network for Constructing a Prognostic Model for Glioblastoma

Abstract

PurposeGlioblastoma (GBM) is one of the most aggressive brain tumors with high mortality, and tumor-derived exosomes provide new insight into the mechanisms of GBM tumorigenesis, metastasis and therapeutic resistance. We aimed to establish an exosome-derived competitive endogenous RNA (ceRNA) network for constructing a prognostic model for GBM.MethodsWe obtained the expression profiles of long noncoding RNAs (lncRNAs), miRNAs, and mRNAs from the GEO and TCGA databases and identified differentially expressed RNAs in GBM to construct a ceRNA network. By performing lasso and multivariate Cox regression analyses, we identified optimal prognosis-related differentially expressed lncRNAs (DElncRNAs) and generated a risk score model termed the exosomal lncRNA (exo-lncRNA) signature. The exo-lncRNA signature was subsequently validated in the CGGA GBM cohort. Finally, a novel prognostic nomogram was constructed based on the exo-lncRNA signature and clinicopathological parameters and validated in the CGGA external cohort. Based on the ceRNA hypothesis, oncocers were identified based on highly positive correlations between lncRNAs and mRNAs mediated by the same miRNAs. Furthermore, regression analyses were performed to assess correlations between the expression abundances of lncRNAs in tumors and exosomes.ResultsA total of 45 DElncRNAs, six DEmiRNAs, and 38 DEmRNAs were identified, and an exosome-derived ceRNA network was built. Three optimal prognostic-related DElncRNAs, HOTAIR (HR=0.341, P<0.001), SOX21-AS1 (HR=0.30, P<0.001), and STEAP3-AS1 (HR=2.47, P<0.001), were included to construct the exo-lncRNA signature, which was further proven to be an independent prognostic factor. The novel prognostic nomogram was constructed based on the exo-lncRNA signature, patient age, pharmacotherapy, radiotherapy, IDH mutation status, and MGMT promoter status, with a concordance index of 0.878. ROC and calibration plots both suggested that the nomogram had beneficial discrimination and predictive abilities. A total of 11 pairs of prognostic oncocers were identified. Regression analysis suggested excellent consistency of the expression abundance of the three exosomal lncRNAs between exosomes and tumor tissues.ConclusionsExosomal lncRNAs may serve as promising prognostic predictors and therapeutic targets. The prognostic nomogram based on the exo-lncRNA signature might provide an intuitive method for individualized survival prediction and facilitate better treatment strategies.

Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA

“…Moreover, STEAP3-AS1 caused the expression of its neighboring STEAP3 in a m 6 A modification-dependent manner, which activated Wnt/β-catenin signaling to support CRC progression. Importantly, recent in silico analysis of a serum exosome-derived ceRNA network has identified STEAP3-AS1 as an independent prognostic predictor of glioblastoma and gallbladder cancer [ 48 , 49 ], further proving its clinic value as a promising biomarker for cancers. Therefore, further studies elucidating the functions of secreted STEAP3-AS1 in CRC progression may expand its applications for early detection or prediction of drug response in CRC patients.…”

Identification of Immune-Related lncRNA Prognostic Signature and Molecular Subtypes for Glioblastoma

“…H19 has a potential reference value for glioma remission and immunotherapy. ST3GAL6-AS1 and SOX21-AS1 as protective factors have been reported in cancers, lncRNA ST3GAL6-AS1 overexpression significantly reduces colorectal cancer cell tumorigenesis and metastasis ( 29 ), and lncRNA SOX21-AS1 significantly suppresses tumorigenesis in cervical cancer ( 30 ), oral cancer ( 31 ), and GBM ( 32 ). Relevant literature reports for AL162231.2 , AC002456.1 , and AC006213.5 are sparse.…”

“…We observed that GBM with GS-A were characterized by four high-risk lncRNAs ( H19 , HOTAIRM1 , AGAP2-AS1 , and AC002456.1 ) and one high-risk mRNA KRT8 with a low expression level. Among these lncRNAs and mRNAs, lncRNA HOXA transcript antisense RNA myeloid-specific 1 ( HOTAIRM1 ) participates in the reprogramming of chromatin organization and proliferation and metastasis of cancer ( 32 ), which has been found to be highly expressed in a variety of tumors including GBM ( 41 ). LncRNA AGAP2 antisense RNA 1 ( AGAP2-AS1 ), transcribed from a gene located at 12q14.1, a novel cancer-related lncRNA, was dysregulated in cancers ( 42 ).…”

Identification of cell cycle as the critical pathway modulated by exosome-derived microRNAs in gallbladder carcinoma

“…STEAP3-AS1 was also identified as a novel, potential prognostic biomarker, and therapeutic target for tongue squamous cell carcinoma (TSCC) [42]. STEAP3-AS1, together with HOTAIR and SOX21-AS1, as the exo-lncRNA signature, was proven to be an independent prognostic factor in glioblastoma (GBM) [43]. MAD2L1, MAD2 mitotic arrest deficient-like 1, is a critical mitotic checkpoint gene.…”