Open Access

ARTICLE

Identification of a Novel Cancer Stemness-Associated ceRNA Axis in Lung Adenocarcinoma via Stemness Indices Analysis

Pihua Han^*†1, Haiming Yang^‡1, Xiang Li^*1, Jie Wu^*, Peili Wang^§, Dapeng Liu^*, Guodong Xiao^¶, Xin Sun^*, Hong Ren^*

* The Second Department of Thoracic Surgery, Cancer Center, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, P.R. China
† Department of Breast Surgery, Shaanxi Provincial Cancer Hospital, Xi’an, P.R. China
‡ Department of Breast Surgery, Wei Nan Central Hospital, Wei Nan, P.R. China
§ Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, P.R. China
¶ Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China

Oncology Research 2020, 28(7-8), 715-729. https://doi.org/10.3727/096504020X16037124605559

Abstract

The aim of this study was to identify a novel cancer stemness-related ceRNA regulatory axis in lung adenocarcinoma (LUAD) via weighted gene coexpression network analysis of a stemness index. The RNA sequencing expression profiles of 513 cancer samples and 60 normal samples were obtained from the TCGA database. Differentially expressed mRNAs (DEmRNAs), lncRNAs (DElncRNAs), and miRNAs (DEmiRNAs) were identified with R software. Functional enrichment analysis was conducted using DAVID 6.8. The ceRNA network was constructed via multiple bioinformatics analyses, and the correlations between possible ceRNAs and prognosis were analyzed using Kaplan–Meier plots. WGCNA was then applied to distinguish key genes related to the mRNA expression-based stemness index (mRNAsi) in LUAD. After combining the weighted gene coexpression and ceRNA networks, a novel ceRNA regulatory axis was identified, and its biological functions were explored in vitro and vivo. In total, 1,825 DElncRNAs, 291 DEmiRNAs, and 3,742 DEmRNAs were identified. Functional enrichment analysis revealed that the DEmRNAs might be associated with LUAD onset and progression. The ceRNA network was constructed with 14 lncRNAs, 10 miRNAs, and 52 mRNAs. Kaplan–Meier analysis identified 2 DEmiRNAs, 5 DElncRNAs, and 41 DEmRNAs with remarkable prognostic power. One gene (MFAP4) in the ceRNA network was found to be closely related to mRNAsi by using WGCNA. Functional investigation further confirmed that the C8orf34-as1/miR-671-5p/MFAP4 regulatory axis has important functions in LUAD cell migration and stemness. This study provides a deeper understanding of the lncRNA–miRNA–mRNA ceRNA network and, more importantly, reveals a novel ceRNA regulatory axis, which may provide new insights into novel molecular therapeutic targets for inhibiting LUAD stem characteristics

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