Новые Гены МикроРНК, Гиперметилированные При Раке Молочной Железы

Логинов, В. И.; Бурденный, А. М.; Пронина, И. В.; Хоконова, В. В.; Kurevlev, S. V.; Казубская, Т. П.; Кушлинский, Н. Е.; Брага, Э. А.

doi:10.7868/s0026898416050104

Cited by 10 publications

(11 citation statements)

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“…Recent studies have shown that Snail and ZEB1 can also reduce cell adhesion, increase cell migratory capacity 76–78 , and promote apoptosis 79,80 . These phenotypic features have also been observed during FECD pathogenesis 81–83 .…”

Section: Discussionmentioning

confidence: 53%

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Pan

Weisenberger

Zheng

et al. 2019

Sci Rep

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Homeostatic maintenance of corneal endothelial cells is essential for maintenance of corneal deturgescence and transparency. in fuchs endothelial corneal dystrophy (fecD), an accelerated loss and dysfunction of endothelial cells leads to progressively severe visual impairment. An abnormal accumulation of extracellular matrix (ecM) is a distinctive hallmark of the disease, however the molecular pathogenic mechanisms underlying this phenomenon are not fully understood. Here, we investigate genome-wide and sequence-specific DNA methylation changes of miRNA genes in corneal endothelial samples from fecD patients. We discover that miRnA gene promoters are frequent targets of aberrant DNA methylation in FECD. More specifically, miR-199B is extensively hypermethylated and its mature transcript miR-199b-5p was previously found to be almost completely silenced in FECD. Furthermore, we find that miR-199b-5p directly and negatively regulates Snai1 and ZEB1, two zinc finger transcription factors that lead to increased ECM deposition in FECD. Taken together, these findings suggest a novel epigenetic regulatory mechanism of matrix protein production by corneal endothelial cells in which miR-199B hypermethylation leads to miR-199b-5p downregulation and thereby the increased expression of its target genes, including Snai1 and ZEB1. our results support miR-199b-5p as a potential therapeutic target to prevent or slow down the progression of FECD disease. Corneal transparency is critical for good visual acuity. The corneal endothelium regulates the hydration status of the cornea and has an essential role in maintaining corneal deturgescence and preventing edema that can degrade corneal transparency. It is the innermost layer of the cornea and is composed of a single layer of cells that pump excess fluid out of the cornea through active ion-transport processes 1,2. Fuchs endothelial corneal dystrophy (FECD) is a bilateral, slowly progressive disorder in which the corneal endothelial cells are diseased and become less efficient at removing fluid. As a result, the highly ordered arrangement of collagen fibers in the corneal stromal layer become disrupted, leading to corneal opacification and vision loss 3. Other clinical phenotypic changes that occur in FECD include an excessive accumulation of extracellular matrix (ECM), formation of central excrescences (corneal guttae), thickening of Descemet's membrane, and corneal scarring 4. At earlier stages of FECD, the formation of corneal guttae can cause light scatter and optical aberrations that can impair vision, even in the absence of overt corneal edema. In later FECD, overt endothelial dysfunction and resultant corneal edema contribute significantly to visual loss. Corneal endothelial cells are largely non-regenerative in vivo and their loss is often irreversible 5. Medical management is often inadequate and corneal endothelial transplantation remains the main therapeutic option to restore vision in patients with advanced FECD. FECD is a leading indication for corneal transplantation i...

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Section: Discussionmentioning

confidence: 53%

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Pan

Weisenberger

Zheng

et al. 2019

Sci Rep

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“…Recent studies have shown that Snail and ZEB1 can also reduce cell adhesion, increase cell migratory capacity [74–76], and promote apoptosis [77, 78]. These phenotypic features have also been observed during FECD pathogenesis [79–81].…”

Section: Discussionmentioning

confidence: 99%

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Pan

Weisenberger

Zheng

et al. 2019

Preprint

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18Homeostatic maintenance of corneal endothelial cells is essential for maintenance of corneal 19 deturgescence and corneal transparency. In Fuchs endothelial corneal dystrophy (FECD), an 20 accelerated loss and dysfunction of endothelial cells leads to progressively severe visual 21impairment. An abnormal accumulation of extracellular matrix is a distinctive hallmark of the 22 disease, however the molecular pathogenic mechanisms underlying this phenomenon are not fully 23 understood. We recently reported characteristic patterns of DNA methylation changes in the 24 corneal endothelial cells of patients with FECD. Here, we investigate genome-wide and sequence-25 specific DNA methylation changes of miRNA genes in corneal endothelial samples derived from 26 patients with FECD. We show that the majority of miRNA genes are hypermethylated at their 27 promoter regions in FECD. More specifically, miR-199B is an extensively hypermethylated 28 miRNA gene at its promoter region and its mature transcript miR-199b-5p was previously found 29 to be almost completely silenced in FECD. Using a cell-based assay, we find that miR-199b-5p 30 directly inhibits the expression of two epithelial mesenchymal transition (EMT)-inducing genes, 31Snai1 and ZEB1. Taken together, these findings suggest a novel regulatory mechanism of matrix 32 protein production by corneal endothelial cells in which miR-199b-5p hypermethylation leads to 33 its down-regulated expression and thereby the decreased expression of miR-199b-5p target genes, 34including Snai1 and ZEB1. Our results support miR-199b-5p as a potential therapeutic target to 35 prevent or slow down the progression of FECD disease. 36 37 Author summary 38 Fuchs endothelial corneal dystrophy (FECD) due to corneal endothelial cell degeneration is one 39 of the most common heritable causes of corneal visual loss and a leading indication for corneal 40 3 transplantation. The progressive loss of corneal endothelial cells is accompanied by an abnormal 41 deposition of extracellular matrix in the form of guttae. Here we discover that miRNA gene 42 promoters are frequent targets of aberrant DNA methylation in FECD. In particular, we describe 43 a novel epigenetic mechanism used by corneal endothelial cells to regulate extracellular matrix 44 production. We find that miRNA-199b-5p functions as a negative regulator of Snai1 and ZEB1, 45 two zinc finger transcription factors that have been shown to lead to increased production of 46 extracellular matrix proteins. Furthermore, miR-199B was extensively hypermethylated in FECD 47 and its mature transcript miR-199b-5p directly binds to the 3′-UTRs of Snai1 and ZEB1 genes. 48Ultimately, this may negatively modulate Snai1-and ZEB1-mediated production of extracellular 49 matrix proteins. This work is the first to identify an important role of DNA methylation in the 50 epigenetic regulation of miRNA-target genes in FECD and to describe a potential epigenetic 51 biomarker for the treatment of FECD patients. 52 53

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“…The promoter CpG islands of miR-130b was not methylated in NSCLC [ 40 ]. However, it had an increased methylation frequency in breast cancer [ 41 ]. The promoter of miR-130b~301b cluster was significantly hepermethylated in prostate cancer tissues compared with morphologically normal ones, which impaired cellular senescence and fuel malignant transformation [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Gga-miR-130b-3p inhibits MSB1 cell proliferation, migration, invasion, and its downregulation in MD tumor is attributed to hypermethylation

Zhao

Han

et al. 2018

Oncotarget

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Marek's disease is an oncogenic and lymphoproliferative disease of chickens caused by Marek's disease virus. Hypermethylation or hypomethylation of CpG islands in gene promoter region are involved in the initiation and progression of carcinogenesis. In this study, we analyzed differential methylation levels of upstream region of gga-miR-130b-3p gene between Marek's disease virus-infected tumorous and non-infected spleens. Around the upstream 1 kb of gga-miR-130b-3p gene, two amplicons were designed that covered 616 bp. There were forty-eight CpG sites in this region. CpG sites in this region presented higher methylation level in tumorous spleens compared with that in non-infected ones. There were eight CpG sites significantly hypermethylated in tumorous spleens. The expression level of three DNA methyltransferases including DNMT1, DNMT3a and DNMT3b increased and the expression level of Tet ten-eleven translocation protein 2 remarkably decreased in tumorous spleens. Hypermethylation in the upstream region of gga-miR-130b-3p gene might be a direct reason for its downregulation in MD tumorous tissues. Moreover, cell proliferation of Marek's disease lymphoblastoid cell line MDCC-MSB1 was remarkably inhibited at 24, 36, 48, 60 and 72 h post-gga-miR-130b-3p-agomir transfection. The transwell migration assay indicated cell number of migration was significantly lower in miRNA agomir transfection group. Matrix metalloproteinases MMP2 and MMP9 are involved in tumor invasion, and their protein levels were significantly downregulated at 72 h post-miRNA-agomir transfection. Collectively, these results indicated that hypermethylation in upstream region of gga-miR-130b-3p gene contributed to its downregulation in tumorous tissues. Gga-miR-130b-3p plays an inhibitory role in lymphomatous cell transformation.

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Новые Гены МикроРНК, Гиперметилированные При Раке Молочной Железы

Cited by 10 publications

References 0 publications

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Gga-miR-130b-3p inhibits MSB1 cell proliferation, migration, invasion, and its downregulation in MD tumor is attributed to hypermethylation

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