Down-regulation of miR-221 and miR-222 correlates with pronounced Kit expression in gastrointestinal stromal tumors

Koelz,

doi:10.3892/ijo.2010.857

Cited by 50 publications

(45 citation statements)

References 47 publications

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“…Up-regulation of mir-222 results in dramatic loss of KIT transcript and c-Kit protein by targeting the 3′-untranslated region (UTR) of KIT in papillary thyroid carcinoma [26], gastrointestinal stromal tumors [27, 28], erythroleukemic cells [29], prostate cancer [30], acute myelogenous leukemia [31], cutaneous melanoma [32] and human umbilical vein endothelial cells (HUVECs) [33]. …”

Section: Resultsmentioning

confidence: 99%

Putative genomic characteristics of BRAF V600K versus V600E cutaneous melanoma

Umbach²,

Li³

2017

Melanoma Research

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Approximately, 50% of all cutaneous melanomas harbor activating BRAF V600 mutations, among these 10–30% carry the V600K mutation. Clinically, patients with V600K tumors experience distant metastases sooner and have an increased risk of relapse and shorter survival than patients with V600E tumors. Despite clinical and other histopathological differences between these BRAF tumor subtypes, little is known about them at the genomic level. Herein, we systematically compared BRAF V600E and V600K skin cutaneous melanoma (SKCM) samples from the Cancer Genome Atlas (TCGA) for differential protein, gene, and microRNA expression genome-wide using the Mann-Whitney U-test. Our analyses showed that elements of energy-metabolism and protein-translation pathways were up-regulated and that pro-apoptotic pathways were down-regulated in V600K tumors compared to V600E tumors. We found that c-Kit protein and KIT gene expressions were significantly higher in V600K tumors than in V600E tumors, concurrent with significant down-regulation of several KIT-targeting microRNAs (mir) including mir-222 in V600K tumors, suggesting KIT and mir-222 might key genomic contributors to observed clinical differences. The relationship that we uncovered among KIT/c-Kit expression, mir-222 expression, and growth and pro-survival signals in V600 tumors is intriguing. We believe that the observed clinical aggressiveness of V600K tumors compared to V600E tumors may be attributable to the increased energy-metabolism, protein-translation and pro-survival signals compared to V600E tumors. If confirmed using larger numbers of V600K tumors, our results may prove useful for designing clinical management and targeted chemotherapeutical interventions for BRAF V600K positive melanomas. Lastly, small sample size in V600K tumors is a major limitation of our study.

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Section: Resultsmentioning

confidence: 99%

Putative genomic characteristics of BRAF V600K versus V600E cutaneous melanoma

Umbach²,

Li³

2017

Melanoma Research

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“…Among the newly associated miRNAs are: miR-200 family members (miR-200c-3p, miR-200a-3p, miR-200b-3p, miR-429, miR-141-3) widely investigated as prognostic and diagnostic biomarkers for cancer [36]; miR-192/215 shown to be involved in cancer-related p53 network [37, 38]; and miR-375 shown to be down-regulated in gastric cancer and to affect cell proliferation [39]. Interestingly, two of the most extensively studied and previously validated miRNAs in GIST – miR-221 and miR-222 [26, 40] – were found to be significantly deregulated in our discovery cohort, but did not meet the selection criteria for validation study and were not further analyzed.…”

Section: Discussionmentioning

confidence: 99%

MiRNA profiling of gastrointestinal stromal tumors by next-generation sequencing

et al. 2017

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Deregulation of miRNAs has been observed virtually in all major types of cancer, whereas the miRNA signature in GIST is not well characterized yet. In this study the first high-throughput miRNA profiling of 15 paired GIST and adjacent normal tissue samples was performed using small RNA-seq approach and differentially expressed miRNAs as well as isomiRNAs were defined. Highly significantly deregulated miRNAs were selected for validation by Taq-Man low-density array in replication group of 40 paired samples. Validated miRNAs were further subjected to enrichment analysis, which revealed significantly enriched KEGG pathways in the main GIST associated pathways. Further, we used an integrated analysis of miRNA-mRNA correlations for KIT and PDGFRA target genes and found a significant correlation between all of the enriched miRNAs and their target gene KIT. Results of the phenotype analysis showed miR-509-3p to be up-regulated in epithelioid and mixed cell types compared to spindle type, whereas miR-215-5p showed negative correlation with risk grade of GIST. These data reveal a detailed miRNA profile of GIST and highlight new candidates that may be important in the development of malignant disease.

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“…In a model of androgen sensitive prostate cancer, researchers found that inhibition of miR-221 in LnCaP cells reduces cell migration [40]. Another study found that miR-221 expression is downregulated in a subset of gastrointestinal stromal tumors, allowing for expression of Kit, and that exogenous miR-221 could act as a putative new therapeutic agent for silencing Kit in these tumors [41]. Research by Felli et al [42] confirm this finding, showing that miR-221 decreases Kit expression in kit-positive leukemic cells.…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis

et al. 2016

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Osteopontin (OPN) promotes hepatic fibrosis, and developing therapies targeting OPN expression in settings of hepatic injury holds promise. The polyphenol epigallocatechin-3-gallate (EGCG), found in high concentrations in green tea, downregulates OPN expression through OPN mRNA degradation, but the mechanism is unknown. Previous work has shown that microRNAs can decrease OPN mRNA levels, and other studies have shown that EGCG modulates the expression of multiple microRNAs. In our study, we first demonstrated that OPN induces hepatic stellate cells to transform into an activated state. We then identified three microRNAs which target OPN mRNA: miR-181a, miR-10b, and miR-221. In vitro results show that EGCG upregulates all three microRNAs, and all three microRNAs are capable of down regulating OPN mRNA when administered alone. Interestingly, only miR-221 is necessary for EGCG-mediated OPN mRNA degradation and miR-221 inhibition reduces the effects of EGCG on cell function. In vivo experiments show that thioacetamide (TAA)-induced cell cytotoxicity upregulates OPN expression; treatment with EGCG blocks the effects of TAA. Furthermore, chronic treatment of EGCG in vivo upregulates all three microRNAs equally, suggesting that in more chronic treatment all three microRNAs are involved in modulating OPN expression. We conclude that in in vitro and in vivo models of TAA-induced hepatic fibrosis, EGCG inhibits OPN-dependent injury and fibrosis. EGCG works primarily by upregulating miR-221 to accelerate OPN degradation. EGCG may therefore have utility as a protective agent in settings of liver injury.

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Down-regulation of miR-221 and miR-222 correlates with pronounced Kit expression in gastrointestinal stromal tumors

Cited by 50 publications

References 47 publications

Putative genomic characteristics of BRAF V600K versus V600E cutaneous melanoma

Putative genomic characteristics of BRAF V600K versus V600E cutaneous melanoma

MiRNA profiling of gastrointestinal stromal tumors by next-generation sequencing

Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis

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