MicroRNA (miR)-211 loss promotes metabolic vulnerability and BRAF inhibitor sensitivity in melanoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE109378 | GEO | 2019/01/02
REPOSITORIES: GEO
Similar Datasets
Project description:Purpose: Identification of miRNAs that enable resistance to BRAF inhibitors in melanoma suggests a mechanism-based strategy to limit resistance and improve clinical outcomes. Methods: We generated A375 melanoma cells resistant to Vemurafenib (VMF) with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Results: Increased expression of miR-204-5p and miR-211-5p occurring in VMF-resistant cells was determined to impact VMF response.
2018-01-18 | GSE107576 | GEO
Project description:mRNA profiles generated from primary fibroblast upon treatment with miR-211, miR-302 or melanoma melanosomes. Abstract: Melanoma originates in the epidermis and enters the metastatic and lethal phase upon invasion into the dermis. However, the interactions between melanoma cells and the dermis prior to this invasion have been poorly studied. Here we uncover that melanoma cells directly affect the formation of the dermal tumor niche by microRNA (miRNA) trafficking prior to invading the dermis. Melanocytes, the cells of melanoma origin, are specialized in trafficking of pigment vesicles, termed melanosomes and, interestingly, melanoma cells retain this trafficking ability. In melanoma in-situ specimens, we found melanosome markers in distal fibroblasts prior to the invasion of melanoma cells into the dermis. Melanoma-derived melanosomes carry miRNAs into primary fibroblasts that trigger changes in the fibroblasts, including increased proliferation, migration, and expression of pro-inflammatory genes, all known features of cancer-associated fibroblasts (CAFs). Specifically, we found that melanosomal miRNA-211 directly targets IGF2R and leads to MAPK signaling activation in fibroblasts, which reciprocally encourages melanoma growth. Treatment of melanoma cells with a melanosome release-inhibitor prevented CAF formation. Since the first interaction of melanoma cells with blood vessels occurs in the dermis, our data suggest a promising opportunity to block melanoma cell invasion by preventing the formation of the dermal tumor niche. In the paper we showed the 10% of most differentially expressed mRNA upon miR-211, miR-320c and melanosomes treatment and overlap of 2000 downregulated mRNA upon miR-211 and melanosomes treatment with predicted target gene miR-211 and CAFs related genes Expresssion profiling was performed for primary fibroblasts transfected with miRNA-211 mimic and miRNA-320c mimic.
2016-08-09 | E-GEOD-72619 | biostudies-arrayexpress
Project description:mRNA profiles generated from primary fibroblast upon treatment with miR-211, miR-302 or melanoma melanosomes. Abstract: Melanoma originates in the epidermis and enters the metastatic and lethal phase upon invasion into the dermis. However, the interactions between melanoma cells and the dermis prior to this invasion have been poorly studied. Here we uncover that melanoma cells directly affect the formation of the dermal tumor niche by microRNA (miRNA) trafficking prior to invading the dermis. Melanocytes, the cells of melanoma origin, are specialized in trafficking of pigment vesicles, termed melanosomes and, interestingly, melanoma cells retain this trafficking ability. In melanoma in-situ specimens, we found melanosome markers in distal fibroblasts prior to the invasion of melanoma cells into the dermis. Melanoma-derived melanosomes carry miRNAs into primary fibroblasts that trigger changes in the fibroblasts, including increased proliferation, migration, and expression of pro-inflammatory genes, all known features of cancer-associated fibroblasts (CAFs). Specifically, we found that melanosomal miRNA-211 directly targets IGF2R and leads to MAPK signaling activation in fibroblasts, which reciprocally encourages melanoma growth. Treatment of melanoma cells with a melanosome release-inhibitor prevented CAF formation. Since the first interaction of melanoma cells with blood vessels occurs in the dermis, our data suggest a promising opportunity to block melanoma cell invasion by preventing the formation of the dermal tumor niche. In the paper we showed the 10% of most differentially expressed mRNA upon miR-211, miR-320c and melanosomes treatment and overlap of 2000 downregulated mRNA upon miR-211 and melanosomes treatment with predicted target gene miR-211 and CAFs related genes
2016-08-09 | GSE72619 | GEO
Project description:MicroRNA (miR)-211 loss promotes metabolic vulnerability and BRAF inhibitor sensitivity in melanoma
| PRJNA430713 | ENA
Project description:Despite increasing amounts of experimental evidence depicting the involvement of non-coding RNAs in cancer, the study of BRAFV600E-regulated genes has thus far focused mainly on protein-coding ones. Here, we identify and study the microRNAs that BRAFV600E regulates through the ERK pathway. By performing small RNA sequencing on A375 melanoma cells and a vemurafenib- resistant clone that was taken as negative control, we discover miR-204 and miR-211 as the miRNAs most induced by vemurafenib. We also demonstrate that, although belonging to the same family, these two miRNAs have distinctive features. miR-204 is under the control of STAT3 and its expression is induced in amelanotic melanoma cells, where it acts as an effector of vemurafenib’s anti-motility activity by targeting AP1S2. Conversely, miR-211, a known transcriptional target of MITF, is induced in melanotic melanoma cells, where it targets EDEM1 and consequently impairs the degradation of TYROSINASE (TYR) through the ER-associated degradation (ERAD) pathway. In doing so, miR-211 serves as an effector of vemurafenib’s pro-pigmentation activity. We also show that such an increase in pigmentation in turn represents an adaptive response that needs to be overcome using appropriate inhibitors in order to increase the ef cacy of vemurafenib. In summary, we unveil the distinct and context-dependent activities exerted by miR-204 family members in melanoma cells. Our work challenges the widely accepted “same miRNA family = same function” rule and provides a rationale for a novel treatment strategy for melanotic melanomas that is based on the combination of ERK pathway inhibitors with pigmentation inhibitors.
2017-03-26 | GSE94476 | GEO
Project description:Despite increasing amounts of experimental evidence depicting the involvement of non-coding RNAs in cancer, the study of BRAFV600E-regulated genes has thus far focused mainly on protein-coding ones. Here, we identify and study the microRNAs that BRAFV600E regulates through the ERK pathway. By performing small RNA sequencing on A375 melanoma cells and a vemurafenib- resistant clone that was taken as negative control, we discover miR-204 and miR-211 as the miRNAs most induced by vemurafenib. We also demonstrate that, although belonging to the same family, these two miRNAs have distinctive features. miR-204 is under the control of STAT3 and its expression is induced in amelanotic melanoma cells, where it acts as an effector of vemurafenib’s anti-motility activity by targeting AP1S2. Conversely, miR-211, a known transcriptional target of MITF, is induced in melanotic melanoma cells, where it targets EDEM1 and consequently impairs the degradation of TYROSINASE (TYR) through the ER-associated degradation (ERAD) pathway. In doing so, miR-211 serves as an effector of vemurafenib’s pro-pigmentation activity. We also show that such an increase in pigmentation in turn represents an adaptive response that needs to be overcome using appropriate inhibitors in order to increase the ef cacy of vemurafenib. In summary, we unveil the distinct and context-dependent activities exerted by miR-204 family members in melanoma cells. Our work challenges the widely accepted “same miRNA family = same function” rule and provides a rationale for a novel treatment strategy for melanotic melanomas that is based on the combination of ERK pathway inhibitors with pigmentation inhibitors.
2017-03-26 | GSE94423 | GEO
Project description:RNA half-life is closely related to its cellular physiological function, so stability determinants may have regulatory functions. Micro(mi)RNAs have primarily been studied with respect to post-transcriptional mRNA regulation and target degradation. Here we study the impact of the tumour suppressive melanoma miRNA miR-211 on transcriptome stability and phenotype in the non-pigmented melanoma cell line, A375. Using 5ʹ-bromouridine IP chase (BRIC)-seq, transcriptome-wide RNA stability profiles revealed highly regulated genes and pathways important in this melanoma cell line. By combining BRIC-seq, RNA-seq and in silico predictions, we identified both existing and novel direct miR-211 targets. We validated DUSP3 as one such novel miR-211 target, which itself sustains colony formation and invasion in A375 cells via MAPK/PI3K signalling. miRNAs have the capacity to control RNA turnover as a gene expression mechanism, and RNA stability profiling is an excellent tool for interrogating functionally relevant gene regulatory pathways and miRNA targets when combined with other high-throughput and in silico approaches.
2019-02-20 | GSE126784 | GEO
Project description:Obesity is a major public health concern that is associated with negative health outcomes. Exercise and dietary restriction are commonly recommended to prevent, or combat obesity. The purpose of this study was to examine the mechanism by which aberrantly expressed genes in the hypothalamic arcuate nucleus (ARC) of diet-induced obese (DIO) rats is attenuated through voluntary exercise. Methods: A transcriptomic approach assessed novel genes in the ARC that affect DIO by voluntary wheel running and a combined approach of physiology, pharmacology, transcriptomic and bioinformatics analysis were used to evaluate the role of miR in the reversal of obesity. Results: Exercise attenuated body weight gain, decreased fat mass, and restored gene expression in the ARC. As high-fat diet (HFD) consumption can cause dysregulation of satiety/hunger regulation mechanisms in the ARC, we outlined transcriptional clusters which depicted alterations in patterns of gene expression through running. Among them were genes involved with inflammation and cellular structure. To uncover regulatory mechanisms governing gene expression in DIO attenuation, we explored the role of miR-211, as it has been implicated in systemic inflammation. The DIO overexpression of miR-211 was ameliorated by exercise, demonstrating its pivotal role in the regulation of inflammation in the ARC. Further, in vivo central administration of miR-211-mimic affected the expression of immunity and cell cycle related genes. By comparing genes attenuated by running and genes downregulated by miR-211, we produced a list of candidate genes that might be involved in the modulation by miR-211 in attenuating obesity by exercise. Conclusion: This research suggests that exercise may have a rescue effect on obesity through changes in gene expression that are mediated partially though miR-211.
2024-07-17 | GSE232510 | GEO
Project description:miR-204-5p and miR-211-5p contribute to BRAF inhibitor resistance in melanoma
| PRJNA420730 | ENA
Project description:In this study, we identified a multi-kinase inhibitor MTX-216 to be efficacious in blocking NF1 loss-of-function melanoma cells. To identify the mechansisms of action of MTX-216, we treated NF1 loss-of-function melanoma cell lines with MTX-216, MTX-211 (the structural analogue of MTX-216 that has no effect on melanoma cells) as well as commericial kinase inhibitors, trametinib and pictilisib, and compared their gene expression profiles.
2022-09-20 | GSE213588 | GEO