A MicroRNA Cluster in the DLK1-DIO3 Imprinted Region on Chromosome 14q32.2 Is Dysregulated in Metastatic Hepatoblastomas

Honda, Susumu; Chatterjee, Aniruddha; Leichter, Anna L.; Miyagi, Hisayuki; Matsushima, Masashi; Fujiyoshi, Sunao; Ara, Momoko; Kitagawa, Norihiko; Tanaka, Mio; Tanaka, Yukichi; Sato, Masato; Hatanaka, Kanako C.; Taketomi, Akinobu; Eccles, Michael R.

doi:10.3389/fonc.2020.513601

Cited by 14 publications

(12 citation statements)

References 32 publications

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“…Moreover, siRNA-mediated inhibition of ASPP2 promotes migration and invasion of HB HuH6 cells. Indeed, treatment with an miR-21 inhibitor induces ASPP2 levels in parallel with a decreased tumor growth in HuH6 cells mouse xenografts [165] . Finally, several miRNAs in the 14q32.2 locus included in the DLK1-DIO3 cluster are upregulated in HB, including lung metastatic HB tumors [166] [Table 3] [147][148][149]152,153,159,161,162,165,[167][168][169][170] .…”

Section: Mirnas In Hbmentioning

confidence: 99%

Epigenetics in hepatoblastoma

Clavería-Cabello¹,

Arechederra²,

Berasain³

et al. 2021

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Hepatoblastoma (HB) is the most frequent pediatric primary liver tumor. When the tumoral lesions can be resected, prognosis is generally favorable. However, there is a significant number of cases in which resection is not possible at diagnosis, and patients usually receive neo-adjuvant cisplatin-based chemotherapy prior to surgery. Unfortunately, some HBs develop resistance to initial chemotherapy or after recurrence, progressing to metastatic disease. Moreover, long-term side effects of chemotherapy remain a serious concern. Understanding the molecular bases of HB development and progression is thus essential for the identification of more efficacious therapies. HBs have a very low mutational burden, and the most frequent mutations occur in the CTNN1B gene (> 80% of cases) and to a lesser extent in NFE2L2 (~10% of cases). These observations suggest that other pathogenic processes besides genetic mutations may play a role in HB tumorigenesis. Epigenetic mechanisms encompass a variety of molecular processes with a tremendous potential to regulate gene expression. They include the covalent modifications of DNA and histones, the activity of enzymatic chromatin remodelers, and the expression of noncoding RNAs. Dysregulation of epigenetic processes has clearly become a hallmark of cancer. Regarding HB, recent studies have explored its epigenetic landscape, the expression of specific epigenetic effectors, and the tumorigenic consequences of epigenetic alterations. The reversible nature of most epigenetic modifications and the possibility to target non-coding RNAs may pave the way for new therapeutic avenues in HB. Here, we summarize and discuss the most relevant findings in this less explored aspect of HB.

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Section: Mirnas In Hbmentioning

confidence: 99%

Epigenetics in hepatoblastoma

Clavería-Cabello¹,

Arechederra²,

Berasain³

et al. 2021

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“…So far, there are 54 miRNAs that have been identified in the human Dlk1-Dio3 region [ 99 ], and 61 miRNAs that have been identified in the murine Dlk1-Dio3 locus [ 101 , 102 ], representing the largest miRNA gene cluster in the human and mouse genome. The epigenetic dysregulation of the Dlk1-Dio3 miRNA cluster has been documented in various cancer types, such as melanoma [ 110 ], leukemia [ 111 ], ovarian cancer [ 112 , 113 ], breast cancer [ 114 ], bladder cancer [ 115 ], metastatic hepatoblastoma [ 116 ], and implicated in tumorigenesis. Recent studies revealed that Dlk1-Dio3 miRNAs are dysregulated in autoimmune disease [ 98 , 103 ] and that the Dlk1-Dio3 locus may play a role in the parent-of-origin effect of autoimmune disease [ 117 ].…”

Section: Genomic Imprinting Dlk1-dio3 Locusmentioning

confidence: 99%

“…The dysregulation of Dlk1-Dio3 miRNAs has been identified in various types of cancers [ 99 , 115 ]. The Dlk1-Dio3 miRNAs have been implicated in the pathogenesis of cancers via targeting key genes in cancer biology, such as phosphatase and tensin homolog ( PTEN ) [ 131 ] and mesenchymal-epithelial transition factor ( c-Met ) [ 115 ], and tumorigenesis signaling pathways such as PI3K/AKT [ 132 ], Hippo signaling, and p53 signaling [ 116 ].…”

Section: Potential Mechanism Of the Dlk1-dio3 Mirnas Involved In Autoimmune Disease Pathogenesismentioning

confidence: 99%

Epigenetic Contribution and Genomic Imprinting Dlk1-Dio3 miRNAs in Systemic Lupus Erythematosus

Dai

Wang

Ahmed

2021

Genes

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Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that afflicts multiple organs, especially kidneys and joints. In addition to genetic predisposition, it is now evident that DNA methylation and microRNAs (miRNAs), the two major epigenetic modifications, are critically involved in the pathogenesis of SLE. DNA methylation regulates promoter accessibility and gene expression at the transcriptional level by adding a methyl group to 5′ cytosine within a CpG dinucleotide. Extensive evidence now supports the importance of DNA hypomethylation in SLE etiology. miRNAs are small, non-protein coding RNAs that play a critical role in the regulation of genome expression. Various studies have identified the signature lupus-related miRNAs and their functional contribution to lupus incidence and progression. In this review, the mutual interaction between DNA methylation and miRNAs regulation in SLE is discussed. Some lupus-associated miRNAs regulate DNA methylation status by targeting the DNA methylation enzymes or methylation pathway-related proteins. On the other hand, DNA hyper- and hypo-methylation are linked with dysregulated miRNAs expression in lupus. Further, we specifically discuss the genetic imprinting Dlk1-Dio3 miRNAs that are subjected to DNA methylation regulation and are dysregulated in several autoimmune diseases, including SLE.

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“…GSE131329 (Hiyama et al, 2019), consisting of 53 HB samples and 14 normal liver samples, was analyzed via GPL6244 platform (Affymetrix Human Gene 1.0 ST Array). GSE153089 (Honda et al, 2020), comprising of 30 HB samples and 14 normal liver samples, was analyzed via GPL21572 platform (Affymetrix Multispecies miRNA-4 Array). General information of the two datasets used for the present study is shown in Supplementary Table 1.…”

Section: Data Retrieval and Extractionmentioning

confidence: 99%

“…The GSE153089 dataset included nine specimens from metastatic tumor, 21 specimens from primary tumor (11 fetal subtypes and 10 embryonal subtypes), and 14 specimens from surrounding normal liver (Honda et al, 2020). Due to the lack of metastatic tumor samples in the GSE131329 dataset (Hiyama et al, 2019), we excluded all specimens from metastatic tumor in the GSE153089 dataset before further analysis.…”

Section: Data Retrieval and Extractionmentioning

confidence: 99%

A Comprehensive Genomic Analysis Constructs miRNA–mRNA Interaction Network in Hepatoblastoma

Chen

Zhao

et al. 2021

Front. Cell Dev. Biol.

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Hepatoblastoma (HB) is a rare disease but nevertheless the most common hepatic tumor in the pediatric population. For patients with advanced HB, the prognosis is dismal and there are limited therapeutic options. Multiple microRNAs (miRNAs) were reported to be involved in HB development, but the miRNA–mRNA interaction network in HB remains elusive. Through a comparison between HB and normal liver samples in the GSE131329 dataset, we detected 580 upregulated differentially expressed mRNAs (DE-mRNAs) and 790 downregulated DE-mRNAs. As for the GSE153089 dataset, the first cluster of differentially expressed miRNAs (DE-miRNAs) were detected between fetal-type tumor and normal liver groups, while the second cluster of DE-miRNAs were detected between embryonal-type tumor and normal liver groups. Through the intersection of these two clusters of DE-miRNAs, 33 upregulated hub miRNAs, and 12 downregulated hub miRNAs were obtained. Based on the respective hub miRNAs, the upstream transcription factors (TFs) were detected via TransmiR v2.0, while the downstream target genes were predicted via miRNet database. The intersection of target genes of respective hub miRNAs and corresponding DE-mRNAs contributed to 250 downregulated candidate genes and 202 upregulated candidate genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated the upregulated candidate genes mainly enriched in the terms and pathways relating to the cell cycle. We constructed protein–protein interaction (PPI) network, and obtained 211 node pairs for the downregulated candidate genes and 157 node pairs for the upregulated candidate genes. Cytoscape software was applied for visualizing the PPI network and respective top 10 hub genes were identified using CytoHubba. The expression values of hub genes in the PPI network were subsequently validated through Oncopression database followed by quantitative real-time polymerase chain reaction (qRT-PCR) in HB and matched normal liver tissues, resulting in six significant downregulated genes and seven significant upregulated genes. The miRNA–mRNA interaction network was finally constructed. In conclusion, we uncover various miRNAs, TFs, and hub genes as potential regulators in HB pathogenesis. Additionally, the miRNA–mRNA interaction network, PPI modules, and pathways may provide potential biomarkers for future HB theranostics.

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A MicroRNA Cluster in the DLK1-DIO3 Imprinted Region on Chromosome 14q32.2 Is Dysregulated in Metastatic Hepatoblastomas

Cited by 14 publications

References 32 publications

Epigenetics in hepatoblastoma

Epigenetics in hepatoblastoma

Epigenetic Contribution and Genomic Imprinting Dlk1-Dio3 miRNAs in Systemic Lupus Erythematosus

A Comprehensive Genomic Analysis Constructs miRNA–mRNA Interaction Network in Hepatoblastoma

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