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The Role of miR-4256/HOXC8 Signaling Axis in the Gastric Cancer Progression: Evidence From lncRNA-miRNA-mRNA Network Analysis

ABSTRACT: Gastric cancer is a deadly human malignancy and the molecular mechanisms underlying gastric cancer pathophysiology are very complicated. Thus, further investigations are warranted to decipher the underlying molecular mechanisms. With the development of high-throughput screening and bioinformatics, gene expression profiles with large scale have been performed in gastric cancer. In the present study, we mined The Cancer Genome Atlas (TCGA) database and analyzed the gene expression profiles between gastric cancer tissues and normal gastric tissues. A series of differentially expressed lncRNAs, miRNAs and mRNAs between gastric cancer tissues and normal gastric tissues were identified. Based on the differentially expressed genes, we constructed miRNA-mRNA network, lncRNA-mRNA network and transcriptional factors-mRNA-miRNA-lncRNA network. Furthermore, the Kaplan survival analysis showed that high expression levels of EVX1, GBX2, GCM1, HOXC8, HOXC9, HOXC10, HOXC11, HOXC12 and HOXC13 were all significantly correlated with shorter overall survival of the patients with gastric cancer. On the other hand, low expression level of HOXA13 was associated with shorter overall survival of patients with gastric cancer. Among these hub genes, we performed the in vitro functional studies of HOXC8 in the gastric cancer cells. Knockdown of HOXC8 and overexpression of miR-4256 both significantly repressed the gastric cancer cell proliferation and migration, and miR-4256 repressed the expression of HOXC8 via targeting its 3’ untranslated region in gastric cancer cells. Collectively, our results revealed that a complex interaction networks of differentially expressed genes in gastric cancer, and further functional studies indicated that miR-4256/HOXC8 may be an important axis in regulating gastric cancer progression.

SUBMITTER: Gu H

PROVIDER: S-EPMC8801578 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Long non-coding RNAs (lncRNAs) are ncRNA transcripts >200 nucleotides that are important genetic regulators. LncRNAs can directly regulate mRNA through a lncRNA-mRNA regulatory mode and can also regulate mRNA through competitive binding to micro (mi)RNA, which is generally known as the competitive endogenous RNA (ceRNA) network. The present study evaluated the functional roles and regulatory networks of lncRNAs in chronic glomerulonephritis (CGN). The proliferative ability of mouse glomerular mesangial cells (GMCs) induced by different concentrations of lipopolysaccharide (LPS) was assessed using the Cell Counting Kit-8 assay, and RNA sequencing (RNA-seq) was performed to identify differentially expressed lncRNAs in LPS-induced GMCs. Based on the sequencing results, six lncRNAs were selected for validation using reverse transcription-quantitative PCR (RT-qPCR). Furthermore, the lncRNA-mRNA regulatory network and the lncRNA-miRNA-mRNA ceRNA network were constructed to assess the role and mechanism of CGN-related lncRNAs. To elucidate the biological functions of lncRNAs, Gene Ontology (GO) biological process term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on all mRNAs involved in the lncRNA-mRNA regulatory network and in the ceRNA network. A total of 1,532 differentially expressed lncRNAs, including 594 upregulated lncRNAs and 938 downregulated lncRNAs, were identified using RNA-seq. The results of RT-qPCR validation were consistent with RNA-seq results. An lncRNA-mRNA regulatory network, including 236 lncRNAs and 556 mRNAs, and a ceRNA network, including 6 lncRNAs, 18 miRNAs and 419 mRNAs, were successfully constructed. The GO biological process term enrichment and KEGG pathway enrichment analyses demonstrated that those lncRNAs were often related to inflammatory response and substance metabolism. The present study identified key CGN-related lncRNAs in LPS-induced GMCs, and further demonstrated a global view of the lncRNA-mRNA regulatory network and ceRNA network involved in CGN. These results offered novel insights into the roles of lncRNAs in the pathogenesis of CGN and identified potential diagnostic biomarkers.

Dataset Information

The Role of miR-4256/HOXC8 Signaling Axis in the Gastric Cancer Progression: Evidence From lncRNA-miRNA-mRNA Network Analysis

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