Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer

Lodygin, Dmitri; Tarasov, Valery; Epanchintsev, Alexey; Berking, Carola; Knyazeva, Tatjana; Körner, Henrike; Knyazev, Piotr; Diebold, Joachim; Hermeking, Heiko

doi:10.4161/cc.7.16.6533

Cited by 717 publications

(577 citation statements)

References 30 publications

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“…Epigenetic regulation by CpG methylation of these miRs could be cell line specific or other epigenetic mechanisms and specific transcriptional factors might interfere with the expression. Bisulfite conversion and methylation-specific PCR supported the existing data and also revealed that miR-34a, miR-199a1, miR-199a2 and miR-199b promoters were hyper-methylated and inversely correlated with their expression in a panel of cancer cells (Lodygin et al, 2008;Garzia et al, 2009;Cheung et al, 2010). Our data shows in particular that miR-199a1 and miR-199b promoters were hypermethylated in NSCLC, BRC and CRC cell lines.…”

Section: Discussionsupporting

confidence: 86%

“…In general, it implies different stages of controlling mechanisms of a gene, especially of an oncogene. Moreover, miR-34a and miR-199a2 are reported that they are epigenetically controlled by CpG methylation (Lodygin et al, 2008;Cheung et al, 2010). 5-Aza treatment significantly induced the expression of either one or all of the miRs (miR-34a, miR-199a and b) in the screened cell lines.…”

Section: Discussionmentioning

confidence: 97%

“…Our data shows in particular that miR-199a1 and miR-199b promoters were hypermethylated in NSCLC, BRC and CRC cell lines. CpG methylation might account for the loss of these three miRs in a substantial portion of carcinomas (Bommer et miR-34a and 199a/b regulates Axl expression G Mudduluru et al Lodygin et al, 2008;Cheung et al, 2010). Our data show that Axl-targeting miRs are epigenetically silenced in cancer cell lines/tumors, and that miR-34a and miR199a/b are regulating Axl expression at mRNA levels by degrading it and also inhibiting translation, which is corroborating the Axl overexpression in different types of cancers (Hafizi and Dahlback, 2006).…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

et al. 2011

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Axl is a receptor that induces proliferation, migration and invasion in cancer. In this study, we show that specific microRNAs (miRNAs) target the 3 0 -UTR of Axl. Luciferase-reporter assays with wild-type and deleted miR-34 and miR-199a/b seed sequences of Axl 3 0 -UTR confirmed the specificity of targeting. An inverse correlation between Axl protein and miR-34a expression in a panel of non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and breast cancer (BRC) cell lines was observed, while miR-199a/b expression was completely suppressed. Pre-miR transfection inhibited in vitro migration and invasion and, in vivo, reduced the number of distant lung-or liver-metastases in a chorion-allantoicmembrane (CAM) assay. Moreover, methylation-specific PCR on bisulfite-converted DNA obtained from the cell lines showed that the miR-34a promoter methylation status was inversely correlated with its expression, and that miR-199a/b promoter regions were methylated in all cells tested. In a panel of NSCLC tissues (n ¼ 44), miR34a and miR-199a/b were found to be downregulated and significantly co-expressed. A lower expression of all three miRs was significantly associated with squamous histotypes, and, in a preliminary series, NSCLC patients with miR-34a upregulation showed a positive association towards a longer survival. These results indicate that Axl receptor expression can be regulated by miR-34a and miR-199a/b, which are suppressed by promoter methylation in solid cancer cells.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

et al. 2011

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“…A literature search using MEDLINE revealed that 16 miRNAs are known to be epigenetically silenced by DNA methylation [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. DNA methylation refers to the covalent addition of a methyl group to the 5-position of cytosines, usually in a CpG dinucleotide context in mammalian differentiated cells [18].…”

Section: Introductionmentioning

confidence: 99%

Identification and Functional Analysis of Epigenetically Silenced MicroRNAs in Colorectal Cancer Cells

et al. 2011

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Abnormal microRNA (miRNA) expression has been linked to the development and progression of several human cancers, and such dysregulation can result from aberrant DNA methylation. While a small number of miRNAs is known to be regulated by DNA methylation, we postulated that such epigenetic regulation is more prevalent. By combining MBD-isolated Genome Sequencing (MiGS) to evaluate genome-wide DNA methylation patterns and microarray analysis to determine miRNA expression levels, we systematically searched for candidate miRNAs regulated by DNA methylation in colorectal cancer cell lines. We found 64 miRNAs to be robustly methylated in HCT116 cells; eighteen of them were located in imprinting regions or already reported to be regulated by DNA methylation. For the remaining 46 miRNAs, expression levels of 18 were consistent with their DNA methylation status. Finally, 8 miRNAs were up-regulated by 5-aza-2′-deoxycytidine treatment and identified to be novel miRNAs regulated by DNA methylation. Moreover, we demonstrated the functional relevance of these epigenetically silenced miRNAs by ectopically expressing select candidates, which resulted in inhibition of growth and migration of cancer cells. In addition to reporting these findings, our study also provides a reliable, systematic strategy to identify DNA methylation-regulated miRNAs by combining DNA methylation profiles and expression data.

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“…miR-34a commonly functions as a tumor suppressor and is down-regulated in many human cancers [11]. Previous studies have revealed that miR-34a is regulated by p53, a tumor suppressor gene [12,13].…”

Section: Micrornas (Mirnas) An Evolutionarily Conserved Class Of Endmentioning

confidence: 99%

Retinoid X receptor α in human liver is regulated by miR-34a

Oda

Nakajima

Tsuneyama

et al. 2014

Biochemical Pharmacology

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Retinoid X receptor α (RXRα) forms a heterodimer with numerous nuclear receptors to regulate drug-or lipid-metabolizing enzymes. In this study, we investigated whether human RXRα is regulated by microRNAs. Two potential recognition elements of miR-34a were identified in the RXRα mRNA: one in the coding region and the other in the 3'-untranslated region (3'-UTR). Luciferase assays revealed that miR-34a recognizes the element in the coding region. The overexpression of miR-34a in HepG2 cells significantly decreased the endogenous RXRα protein and mRNA levels. The stability of RXRα mRNA was decreased by the overexpression of miR-34a, indicating that miR-34a negatively regulates RXRα expression by facilitating mRNA degradation. We found that the miR-34a-dependent down-regulation of RXRα decreases the induction of CYP26 and the transactivity of CYP3A4. miR-34a has been reported to be up-regulated by p53, which has an ability to promote liver fibrosis. The p53 activation resulted in an increase of the miR-34a level and a decrease of the RXRα protein level. In addition, the miR-34a levels in eight fibrotic livers were higher than those in six normal livers, and the reverse trend was found for the RXRα protein levels. An inverse correlation was observed between the miR-34a and the RXRα protein levels in the 14 samples. Taken together, the data show that miR-34a negatively regulates RXRα expression in human liver, and affects the expression of its downstream genes. This miR-34a-dependent regulation might be the underlying mechanism responsible for the decreased expression of the RXRα protein in fibrotic livers.

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Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer

Cited by 717 publications

References 30 publications

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

Identification and Functional Analysis of Epigenetically Silenced MicroRNAs in Colorectal Cancer Cells

Retinoid X receptor α in human liver is regulated by miR-34a

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