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Regulatory function of DNA methylation mediated lncRNAs in gastric cancer.

ABSTRACT: As one of the most common malignancies worldwide, gastric cancer contributes to cancer death with a high mortality rate partly responsible for its out-of-control progression as well as limited diagnosis. DNA methylation, one of the epigenetic events, plays an essential role in the carcinogenesis of many cancers, including gastric cancer. Long non-coding RNAs have emerged as the significant factors in the cancer progression functioned as the oncogene genes, the suppressor genes and regulators of signaling pathways over the decade. Intriguingly, increasing reports, recently, have claimed that abnormal DNA methylation regulates the expression of lncRNAs as tumor suppressor genes in gastric cancer and lncRNAs as regulators could exert the critical influence on tumor progression through acting on DNA methylation of other cancer-related genes. In this review, we summarized the DNA methylation-associated lncRNAs in gastric cancer which play a large impact on tumor progression, such as proliferation, invasion, metastasis and so on. Furthermore, the underlying molecular mechanism and signaling pathway might be developed as key points of gastric cancer range from diagnosis to prognosis and treatment in the future.

SUBMITTER: Li N

PROVIDER: S-EPMC9270757 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Regulatory function of DNA methylation mediated lncRNAs in gastric cancer.

Li Nan N Zeng Anqi A Wang Qian Q Chen Maohua M Zhu Shaomi S Song Linjiang L

Cancer cell international 20220709 1

As one of the most common malignancies worldwide, gastric cancer contributes to cancer death with a high mortality rate partly responsible for its out-of-control progression as well as limited diagnosis. DNA methylation, one of the epigenetic events, plays an essential role in the carcinogenesis of many cancers, including gastric cancer. Long non-coding RNAs have emerged as the significant factors in the cancer progression functioned as the oncogene genes, the suppressor genes and regulators of ...[more]

PMID: 35810299

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Project description:Background: The prognosis of gastric cancer (GC) patients is poor. The effect of aberrant DNA methylation on FOXF2 expression and the prognostic role of FOXF2 methylation in GC have not yet been identified. Methods: The RNA-Seq and gene methylation HM450 profile data were used for analyzing FOXF2 expression in GC and its association with methylation level. Bisulfite sequencing PCR (BSP) was performed to measure the methylation level of the FOXF2 promoter region in GC cell lines and normal GES-1 cells. The cells were treated with the demethylation reagent 5-Aza-dC, and the mRNA and protein expression levels of FOXF2 were then measured by qRT-PCR and western blot assays. The risk score system from SurvivalMeth was calculated by integrating the methylation level of the cg locus and the corresponding Cox regression coefficient. Results: FOXF2 was significantly downregulated in GC cells and tissues. On the basis of RNA-Seq and Illumina methylation 450 data, FOXF2 expression was significantly negatively correlated with the FOXF2 methylation level (Pearson's R = -0.42, p < 2.2e-16). The FOXF2 methylation level in the high FOXF2 expression group was lower than that in the low FOXF2 expression group. The BSP assay indicated that the methylation level of the FOXF2 promoter region in GC cell lines was higher than that in GES-1 cells. The qRT-PCR and western blot assay showed that FOXF2 mRNA and protein levels were increased in GC cells following treatment with 5-Aza-Dc. The methylation risk score model indicated that patients in the high risk group had poorer survival probability than those in the low risk group (HR = 1.84 (1.11-3.07) and p = 0.0068). FOXF2 also had a close transcriptional regulation network with four miRNAs and their corresponding target genes. Functional enrichment analysis of the target genes revealed that these genes were significantly related to several important signaling pathways. Conclusion: FOXF2 was downregulated due to aberrant DNA methylation in GC, and the degree of methylation in the promoter region of FOXF2 was related to the prognosis of patients. The FOXF2/miRNAs/target genes axis may play a vital biological regulation role in GC.

Project description:BackgroundStomach adenocarcinoma (STAD) is one of the most common and deadly cancers worldwide. Recent evidence has demonstrated that dysregulation of long noncoding RNAs (lncRNA) is associated with different hallmarks of cancer. lncRNAs also were suggested as novel promising biomarkers for cancer diagnosis and prognosis. Despite these previous investigations, the expression pattern, diagnostic role, and hallmark association of lncRNAs in STAD remain unclear.ResultsIn this study, The STAD lncRNA-mRNA network was constructed based on RNAs that differentially expressed among tumor and normal samples and had a strong expression correlation with others. The high degree nodes of the network were associated with overall survival. In addition, we found that the hubs' regulatory roles have previously been confirmed in different types of cancers by literature. For example, the HCG22 hub inhibited cell proliferation and invasion and induced apoptosis in oral squamous cell carcinoma (OSCC) cells. The levels of PCNA, Vimentin, and Bcl2 were decreased and E-cadherin and Bax expression was elevated in OSCC cells after HCG22 overexpression. Additionally, HCG22 overexpression inhibited the Akt, mTOR, and Wnt/β-catenin pathways. Then lncRNAs were mapped to their related GO terms and cancer hallmarks. Based on these mappings, we predict the hallmarks that might be associated with each lncRNA. Finally, the literature review confirmed our prediction. Among the 20 lncRNAs of the STAD network, 11 lncRNAs (LINC02560, SOX21-AS1, C5orf66-AS1, HCG22, PGM5-AS1, NALT1, ENSG00000241224.2, TINCR, MIR205HG, HNF4A-AS1, ENSG00000262756) demonstrated expression correlation with overall survival (OS). Based on expression analysis, survival analysis, hallmark associations, and literature review, LINC02560, SOX21-AS1, C5orf66-AS1, HCG22, PGM5-AS1, NALT1, ENSG00000241224.2, TINCR, MIR205HG, HNF4A-AS1 plays a regulatory role in STAD. For example, our prediction of association between C5orf66-AS1 expression dysregulation and "sustaining proliferative signal" and "Activating invasion and metastasis" has been confirmed in STAD, OSCC and cervical cancer. Finally, we developed a lncRNA signature with SOX21-AS1 and LINC02560, which classified patients into high and low-risk subgroups with significantly different survival outcomes. The mortality rate of the high-risk patients was significantly higher compared to the low-risk patients (28/1% vs 60.13).ConclusionThese findings help in designing more precise and detailed experimental studies to find STAD biomarkers and therapeutic targets.

Project description:BackgroundFew studies have examined prognostic outcomes-associated molecular signatures other than overall survival (OS) for gastric cancer (GC). We aimed to identify DNA methylation biomarkers associated with multiple prognostic outcomes of GC in an epigenome-wide association study.MethodsBased on the Cancer Genome Atlas (TCGA), DNA methylation loci associated with OS (n = 381), disease-specific survival (DSS, n = 372), and progression-free interval (PFI, n = 383) were discovered in training set subjects (false discovery rates < 0.05) randomly selected for each prognostic outcome and were then validated in remaining subjects (P-values < 0.05). Key CpGs simultaneously validated for OS, DSS, and PFI were further assessed for disease-free interval (DFI, n = 247). Gene set enrichment analyses were conducted to explore the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways simultaneously enriched for multiple GC prognostic outcomes. Methylation correlated blocks (MCBs) were identified for co-methylation patterns associated with GC prognosis. Based on key CpGs, risk score models were established to predict four prognostic outcomes. Spearman correlation analyses were performed between key CpG sites and their host gene mRNA expression.ResultsWe newly identified DNA methylation of seven CpGs significantly associated with OS, DSS, and PFI of GC, including cg10399824 (GRK5), cg05275153 (RGS12), cg24406668 (MMP9), cg14719951(DSC3), and cg25117092 (MED12L), and two in intergenic regions (cg11348188 and cg11671115). Except cg10399824 and cg24406668, five of them were also significantly associated with DFI of GC. Neuroactive ligand-receptor interaction pathway was suggested to play a key role in the effect of DNA methylation on GC prognosis. Consistent with individual CpG-level association, three MCBs involving cg11671115, cg14719951, and cg24406668 were significantly associated with multiple prognostic outcomes of GC. Integrating key CpG loci, two risk score models performed well in predicting GC prognosis. Gene body DNA methylation of cg14719951, cg10399824, and cg25117092 was associated with their host gene expression, whereas no significant associations between their host gene expression and four clinical prognostic outcomes of GC were observed.ConclusionsWe newly identified seven CpGs associated with OS, DSS, and PFI of GC, with five of them also associated with DFI, which might inform patient stratification in clinical practices.

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Regulatory function of DNA methylation mediated lncRNAs in gastric cancer.

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Regulatory function of DNA methylation mediated lncRNAs in gastric cancer.

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