Aberrant methylation of miR-124 upregulates DNMT3B in colorectal cancer to accelerate invasion and migration

Shahmohamadnejad, Shiva; Ghonbalani, Zahra Nouri; Tahbazlahafi, Behnoosh; Panahi, Ghodratollah; Meshkani, Reza; Razavi, Àmirnader Emami; Afra, Hajar Shokri; Khalili, Ehsan

doi:10.1080/13813455.2020.1779311

Cited by 17 publications

(15 citation statements)

References 46 publications

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“…Depending on the genes targeted, miRs could have both oncogenic or tumor-suppressor functions. This is evident from several studies in CRC as well as in other solid carcinoma [14,15,17,36,39,58,60,71,73]. Importantly, the expression of any miR is only one factor to define its netto influence on its target genes; other parameters are, e.g., the specificity of interaction of the miR with its target mRNA (seed) sequence, the accessibility of the target mRNA for the microRNA by, for example, intracellular compartmentalization, and others [7,9,74].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, hypermethylation was more evident in protein-coding genes, but the reverse was the case in non-coding regions, leading to the hypothesis that epigenetic alterations in coding and non-coding sequences might cooperate in human tumorigenesis. In line with the objectives of our study, we proceeded to specifically evaluate miR genes, many of which have been shown to regulate CRC progression and metastasis [ 14 , 36 , 37 , 40 , 42 , 43 , 54 , 60 , 65 , 66 , 68 , 69 , 83 ]. For miR genes, differential methylation was observed predominantly in the open seas and CpG islands.…”

Section: Discussionmentioning

confidence: 99%

“…Many of these miRs we found significantly differentially methylated in CRC also already have been shown to take functional roles in diverse further cancer entities besides CRC, which were in part related to changes in the methylation of their genes. For example, a tumor-suppressor function has been ascribed to all three loci encoding mature hsa-miR-124 (hsa-miR-124-1/-2/-3), which has been shown to be hypermethylated in cervical tumors [ 30 ], prostate cancer [ 31 ], nasopharyngeal carcinoma [ 85 ], HCC [ 32 , 33 ], bladder cancer [ 34 ], and CRC [ 35 , 36 , 37 ]. Likewise, mature miR-129-2 miR has been shown to be a tumor suppressor in esophageal cancer [ 38 ], breast cancer [ 39 ], and CRC [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

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Changes in Methylation across Structural and MicroRNA Genes Relevant for Progression and Metastasis in Colorectal Cancer

Patil

Abba

Zhou

et al. 2021

Cancers

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MiRs are important players in cancer and primarily genetic/transcriptional means of regulating their gene expression are known. However, epigenetic changes modify gene expression significantly. Here, we evaluated genome-wide methylation changes focusing on miR genes from primary CRC and corresponding normal tissues. Differentially methylated CpGs spanning CpG islands, open seas, and north and south shore regions were evaluated, with the largest number of changes observed within open seas and islands. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed several of these miRs to act in important cancer-related pathways, including phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) pathways. We found 18 miR genes to be significantly differentially methylated, with MIR124-2, MIR124-3, MIR129-2, MIR137, MIR34B, MIR34C, MIR548G, MIR762, and MIR9-3 hypermethylated and MIR1204, MIR17, MIR17HG, MIR18A, MIR19A, MIR19B1, MIR20A, MIR548F5, and MIR548I4 hypomethylated in CRC tumor compared with normal tissue, most of these miRs having been shown to regulate steps of metastasis. Generally, methylation changes were distributed evenly across all chromosomes with predominance for chromosomes 1/2 and protein-coding genes. Interestingly, chromosomes abundantly affected by methylation changes globally were rarely affected by methylation changes within miR genes. Our findings support additional mechanisms of methylation changes affecting (miR) genes that orchestrate CRC progression and metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Changes in Methylation across Structural and MicroRNA Genes Relevant for Progression and Metastasis in Colorectal Cancer

Patil

Abba

Zhou

et al. 2021

Cancers

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“…From the correlation analysis, we found the expression levels of some prognosis-related pseudogenes were signi cantly correlated with many prognosis-related protein-coding genes that had been reported to play roles in CRC and other kinds of cancers. For example, pseudogene DDX12P and FER1L4 were positively correlated with DNMT3B which was an important tumor associated gene and aberrantly expressed or mutant in many kinds of cancers [27,28]. Pseudogene GVINP1 and NCF1C highly correlated with the expression levels of many mRNAs such as PDGFRA, ENPP2, HAPLN1, SOCS6 and SNCG, they had all been reported to participate in the tumorigenesis and progression of CRC in many studies [29][30][31][32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Construction of a Pseudogene‐associated ceRNA Network and Identification of Prognostic Pseudogene Biomarkers for Colorectal Cancer

Zhou

et al. 2021

Preprint

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Colorectal cancer (CRC) is one of the most common and deadly malignant carcinomas. Many long noncoding RNAs (lncRNA) have been reported to play an important role in the tumorigenesis of CRC by interacting with miRNAs and influencing the expression of some mRNAs through a competing endogenous RNA (ceRNA) network. Pseudogenes are one kind of lncRNA and can act as RNA sponges for miRNAs and regulate gene expression via ceRNA networks, but there are few studies about pseudogenes in CRC. In this study, total of 31 differentially expressed (DE) pseudogenes, 17 DE miRNAs and 152 DE mRNAs were identified by analyzing the expression profiles of colon adenocarcinoma (COAD) obtained from The Cancer Genome Atlas (TCGA). And a ceRNA network was constructed based on these RNAs. Kaplan–Meier analysis showed that 7 pseudogenes, 4 miRNAs and 30 mRNAs were significantly associated with overall survival. Then multivariate Cox regression analysis on the ceRNA-related DE pseudogenes was performed and a 5-pseudogene signature with the greatest prognostic value for CRC was identified. What’s more, the results were validated by the Gene Expression Omnibus (GEO) database, and quantitative real‐time PCR (qRT‐PCR) in 113 pairs of CRC tissues. In conclusion, this study provides a pseudogene-associated ceRNA network and 7 prognostic pseudogene biomarkers, and a 5-pseudogene prognostic risk signature that may be useful to predict the survival of CRC patients.

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“…Studies have shown that some tumor suppressor genes (TSGs) in various cancers have been muted due to abnormal hypermethylation of the promoter. It has also been shown that some miRNAs, such as TSG, have an abnormal pattern of hypermetylation in their promoter, which leads to reducing the TSG activity and over-expressing the oncogenic targets [10][11][12][13]. In this regard, several studies have reported that miRNA-424 expression pattern has changed in colorectal cancer [15], and it has been shown that this miRNA inhibits the angiogenesis and the growth of the cancerous tissue by targeting the Vascular endothelial growth factor (VEGF) protein [14,15].…”

Section: Introductionmentioning

confidence: 99%

Hypermethylated miR-424 in Colorectal Cancer Subsequently Upregulates VEGF

Ghonbalani

Shahmohamadnejad

Pasalar

et al. 2021

J Gastrointest Canc

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Purpose Colorectal cancer (CRC) is the second leading cause of death from cancer in adults. Recent advances have shown that cancer cells can have some epigenetic changes involved in all stages of cancer. It has also been shown that miR-424 acts as gene expression regulators in many biological processes, including angiogenesis with mediators such as VEGF. In the current study, to identify the potential role of miR-424 in colorectal cancer progression, methylation status of miR-424 promoter region and its expression level have been evaluated. Besides, the correlation between VEGF level and miR-424 expression level has been assessed. Methods Methylation status miR-424 promoter was assessed using methylation-speci c polymerase chain reaction (MSP). The expression level of miR-424 in human colorectal cancer tissue was analyzed by quantitative PCR. HCT116 cell line was selected to evaluate the correlation between the miR-424 expression level and the promoter's methylation status. VEGF expression, one out of mir-424 targets involved in angiogenesis and cancer progression, was measured by western blot analysis in the pairs of cancer tissues and their adjacent tissues. Results Our results have revealed that the promoter region of miR-424 is methylated in cancer cells compared to normal cells, leading to down-regulation of miR-424 in the colorectal cancer tissues compared to the normal tissues. Also, we found that the expression protein's level of VEGF in the tumor cells increased compared with normal tissues. Conclusion The present study suggests that hypermethylation downregulates miR-424. VEGF expression is upregulated with decreased miR-424 in colorectal cancer, which results in cancer progression.

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Aberrant methylation of miR-124 upregulates DNMT3B in colorectal cancer to accelerate invasion and migration

Cited by 17 publications

References 46 publications

Changes in Methylation across Structural and MicroRNA Genes Relevant for Progression and Metastasis in Colorectal Cancer

Changes in Methylation across Structural and MicroRNA Genes Relevant for Progression and Metastasis in Colorectal Cancer

Construction of a Pseudogene‐associated ceRNA Network and Identification of Prognostic Pseudogene Biomarkers for Colorectal Cancer

Hypermethylated miR-424 in Colorectal Cancer Subsequently Upregulates VEGF

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