Epigenetic modifications in gastric cancer: Focus on DNA methylation

Ebrahimi, Vida; Soleimanian, Alireza; Ebrahimi, Tahereh; Azargun, Robab; Yazdani, Parivar; Eyvazi, Shirin; Tarhriz, Vahideh

doi:10.1016/j.gene.2020.144577

Cited by 70 publications

(60 citation statements)

References 57 publications

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“…Particularly, we nd that DNA methylation status is inversely correlated with the mRNA expression of several ARLs in GC. It is generally accepted that DNA methylation is a major epigenetic process that plays a critical role in different stages of cancer evolution and development (29). Fujii's study showed that the hypomethylation in the 3'-UTR induces the overexpression of ARL4C in lung cancer which contributes to the malignant phenotypes of cancer cells (22).…”

Section: Discussionmentioning

confidence: 99%

ARL4C is A Key Driver of Gastric Cancer: An Integrative Analysis of ARL Family Members

Xie¹,

Bai²,

Lu³

et al. 2020

Preprint

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Background: As small GTP-binding proteins, ARL family members (ARLs) have been proved to regulate the malignant phenotypes of several cancers. However, the exact role of ARLs in gastric cancer (GC) remains elusive.Methods: The expression status, interactive relations, potential pathways and genetic variations of ARLs are analyzed by bioinformatics tools. Machine learning models and enrichment analysis are performed by R platform. The biological functions of ARL4C are demonstrated by in vitro and in vivo experiments. The nomogram is further constructed to validate the prognostic value of ARL4C for GC patients.Results: ARLs are significantly dysregulated in GC and involved in various cancer-related pathways. Subsequently, machine learning models identify ARL4C as one of the two most significant diagnostic and prognostic indicators among ARLs for GC. Furthermore, ARL4C silencing remarkably reverses the epithelial-mesenchymal transition (EMT) and inhibits the growth and metastasis of GC cells both in vitro and in vivo. Moreover, enrichment analysis indicates that TGF-β1 is highly correlated with ARL4C, while ARL4C-related genes are significantly enriched in the TGF-β1 signaling. Correspondingly, we demonstrate that TGF-β1 treatment dramatically increases ARL4C expression, and ARL4C knockdown reverses TGF-β1-induced EMT possibly by inhibiting the expression of Smads, downstream factors of TGF-β1. Meanwhile, the coexpression of ARL4C and TGF-β1 worsens the prognosis of GC patients both in Kaplan-Meier analysis and nomogram model.Conclusion: Our work is of significance for comprehensively understanding the crucial role of ARLs in the carcinogenesis of GC and the specific mechanisms underlying the GC-promoting effects of TGF-β1. More importantly, we uncover the great promise of ARL4C-targeted therapy in improving the efficacy of TGF-β1 inhibitors for GC patients.

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Section: Discussionmentioning

confidence: 99%

ARL4C is A Key Driver of Gastric Cancer: An Integrative Analysis of ARL Family Members

Xie¹,

Bai²,

Lu³

et al. 2020

Preprint

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“…The main cause of GC is helicobacter pylori (H. pylori) infection, which may lead to chronic inflammation and consequently tumorigenesis [ 4 ]. In addition to H. pylori infection, other risk factors such as environmental, genetic, and epigenetic factors have also been identified [ 5 ]. Although the etiology, clinical characteristics, and classifications have previously been described in detail, the same treatment methods are routinely applied for all patients with GC despite the complex genetic heterogeneity of the disease, which can result in poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Epigenetic changes mainly include DNA methylation, non-coding RNA, chromatin remodeling, and histone modifications [ 5 ]. These factors can regulate the expression of genes without DNA sequence changes and are inheritable across generations [ 5 ]. DNA methylation is a well-characterized epigenetic modification and plays an important role in carcinogenesis [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Identification of the subtypes of gastric cancer based on DNA methylation and the prediction of prognosis

Chen

et al. 2020

Clin Epigenet

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Background Gastric cancer (GC) is a digestive system cancer with a high mortality rate globally. Previous experiences and studies have provided clinicians with ample evidence to diagnose and treat patients with reasonable therapeutic options. However, there remains a need for sensitive biomarkers that can provide clues for early diagnosis and prognosis assessment. Results We found 610 independent prognosis-related 5′-cytosine-phosphate-guanine-3′ (CpG) sites (P < 0.05) among 21,121 sites in the training samples. We divided the GC samples into seven clusters based on the selected 610 sites. Cluster 6 had relatively higher methylation levels and high survival rates than the other six clusters. A prognostic risk model was constructed using the significantly altered CpG sites in cluster 6 (P < 0.05). This model could distinguish high-risk GC patients from low-risk groups efficiently with the area under the receiver operating characteristic curve of 0.92. Risk assessment showed that the high-risk patients had poorer prognosis than the low-risk patients. The methylation levels of the selected sites in the established model decreased as the risk scores increased. This model had been validated in testing group and its effectiveness was confirmed. Corresponding genes of the independent prognosis-associated CpGs were identified, they were enriched in several pathways such as pathways in cancer and gastric cancer. Among all of the genes, the transcript level of transforming growth factor β2 (TGFβ2) was changed in different tumor stages, T categories, grades, and patients’ survival states, and up-regulated in patients with GC compared with the normal. It was included in the pathways as pathways in cancer, hepatocellular carcinoma or gastric cancer. The methylation site located on the promoter of TGFβ2 was cg11976166. Conclusions This is the first study to separate GC into different molecular subtypes based on the CpG sites using a large number of samples. We constructed an effective prognosis risk model that can identify high-risk GC patients. The key CpGs sites or their corresponding genes such as TGFβ2 identified in this research can provide new clues that will enable gastroenterologists to make diagnosis or personalized prognosis assessments and better understand this disease.

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“…The methylation of CpG islands can recruit repressive methyl-binding proteins, impair transcription factor binding, and condense chromatin structure [11,12] . Therefore, CpG islands are generally methylated in promoters of silencing genes and not methylated in transcriptionally active genes [13] . Furthermore, abnormal hypomethylation of oncogenes and hypermethylation of tumor suppressor genes have been found to play important roles in human tumorigenesis and cancer progression, including those of RC [14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of DNA methylation and gene expression profiles in rectal cancer

Zhang¹,

Meng²,

Chao³

et al. 2020

Preprint

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BackgroundAbnormal hypomethylation of oncogenes and hypermethylation of tumor suppressor genes play important roles in human tumorigenesis and cancer progression, including those of rectal cancer (RC). However, conjoint analysis of RC involving both gene expression and methylation profiling datasets remains rare. This study aimed to identify methylation-regulated differentially expressed genes (MeDEGs) and to evaluate their prognostic value in RC through bioinformatics analysis.MethodsGene expression (GSE20842 and GSE68204) and gene methylation (GSE75546) profiling datasets were obtained from the Gene Expression Omnibus database. GEO2R was adopted to identify differentially expressed genes (DEGs) and differentially methylated genes (DMGs). MeDEGs were obtained by overlapping the DEGs and DMGs and then subjected to protein–protein interaction (PPI) network analysis using STRING. Modules and hub genes within the network were identified using MCODE and CytoHubba, respectively. Prognostic MeDEGs were selected by univariate Cox regression. Finally, our findings were validated based on The Cancer Genome Atlas (TCGA) database.ResultsIn total, 243 upregulated-hypomethylated and 51 downregulated-hypermethylated genes were identified as MeDEGs. A PPI network of MeDEGs was constructed with 290 nodes and 578 edges. Three modules and three hub genes—COL3A1, FPR1, and PLK1—within the network were identified. Three MeDEGs—NFE2, COMP, and LAMA1—were found to be survival-related. Furthermore, the expression and methylation status of two hub genes (excluding FPR1) and the three prognostic MeDEGs were also significantly altered in TCGA and were consistent with our findings.ConclusionsWe identified novel MeDEGs and explored their relationship with survival in RC. Our methodology may provide an effective bioinformatics basis for further understanding of the methylation-mediated regulatory mechanisms in RC.

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Epigenetic modifications in gastric cancer: Focus on DNA methylation

Cited by 70 publications

References 57 publications

ARL4C is A Key Driver of Gastric Cancer: An Integrative Analysis of ARL Family Members

ARL4C is A Key Driver of Gastric Cancer: An Integrative Analysis of ARL Family Members

Identification of the subtypes of gastric cancer based on DNA methylation and the prediction of prognosis

Comprehensive analysis of DNA methylation and gene expression profiles in rectal cancer

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