MiR-146 connects stem cell identity with metabolism and pharmacological resistance in breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA545160 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9139870.fastq.gz | Fastqsanger.gz | |||
| SRR9139871.fastq.gz | Fastqsanger.gz | |||
| SRR9139872.fastq.gz | Fastqsanger.gz | |||
| SRR9139873.fastq.gz | Fastqsanger.gz | |||
| SRR9139868.fastq.gz | Fastqsanger.gz |
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Project description:Although ectopic overexpression of miRNAs can influence mammary normal and cancer stem cells (SCs/CSCs), their physiological relevance remains uncertain. Here, we found that the miR-146 family is linked to SC identity, since: i) their expression is very high in SCs/CSCs from human/mouse primary mammary tissues; correlates with the basal-like breast cancer subtype, which typically has a high CSC content; and specifically distinguishes cells with SC/CSC identity; ii) miR-146 depletion reduces SC/CSC self-renewal in vitro and the number of tumor-initiating cells in vivo. Analysis of the transcriptional effects of miR-146 in breast SC-like cells revealed a complex network of highly connected miR-146 targets related to quiescence, transcription and metabolic pathways (one-carbon pool, purine synthesis and folate metabolism). As predicted by our analysis, SCs/CSCs display innate resistance to anti-folate therapy that can be reversed by miR-146 depletion, unmasking a “hidden vulnerability” that could be exploited for the development of anti-CSC therapies.
2020-01-21 | GSE131876 | GEO
Project description:Although ectopic overexpression of miRNAs can influence mammary normal and cancer stem cells (SCs/CSCs), their physiological relevance remains uncertain. Here, we show that miR-146 is relevant for SC/CSC activity. MiR-146a/b expression is high in SCs/CSCs from human/mouse primary mammary tissues, correlates with the basal-like breast cancer subtype, which typically has a high CSC content, and specifically distinguishes cells with SC/CSC identity. Loss of miR-146 reduces SC/CSC self-renewal in vitro and compromises patient-derived xenograft tumor growth in vivo, decreasing the number of tumor-initiating cells, thus supporting its pro-oncogenic function. Transcriptional analysis in mammary SC-like cells revealed that miR-146 has pleiotropic effects, reducing adaptive response mechanisms and activating the exit from quiescent state, through a complex network of finely regulated miRNA targets related to quiescence, transcription, and one-carbon pool metabolism. Consistent with these findings, SCs/CSCs display innate resistance to anti-folate chemotherapies either in vitro or in vivo that can be reversed by miR-146 depletion, unmasking a "hidden vulnerability" exploitable for the development of anti-CSC therapies.
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Project description:MicroRNAs (miRNAs) are evolutionary conserved, non-coding, gene regulatory RNA molecules found in both plants and animals and amongst almost every cell and tissue type. They are about 22 nucleotides long and are involved in silencing of mRNA through sequence specific binding to the 3’ untranslated region (UTR) of the mRNA subsequently causing translational repression and/or will promote the degradation of protein-coding mRNA. Specifically, the miRNA family, mir-146 a/b, has been previously found to be involved in the regulation of the innate immune response by functioning as a negative regulator to help fine-tune the immune response. Microglial cells are the macrophage of the brain participating as major players of the innate immune response. During prion disease, no immune response is mounted against PrPSc possibly due to its similarity to host PrPc and thus, the host immune response would be suppressed and tightly regulated. Therefore, an increased expression of mir-146 by microglial cells during prion disease may function as one of these negative regulators. Our objective of this experiment is to use DNA microarrays to investigate the gene regulation of mir-146 previously found upregulated in our studies of mouse brain tissue specifically in microglial cells during prion disease with the aim of having a better understanding of prion pathobiology and a potential target for therapeutic intervention. Mir-146 expression was confirmed via in situ analysis of brain tissue and was further investigated in a microglial murine cell line (EOC 13.31). To mimic mir-146 upregulation during prion disease, mir-146 a & b were overexpressed in EOCs using a lipid based reverse transfection system. Furthermore, endogeneous mir-146 was knocked down as another method to help confirm the mRNA targets affected by mir-146. Simultaneously, another experiment was performed for the investigation of its involvement in the innate immune response by stimulating the EOCs with differing concentrations of LPS from E.coli (055:B5). Total RNA was collected and prepared at several timepoints and the levels of expression of both mir-146 a & b was tested via qRT-PCR. The RNA collected from the EOCs from each condition were used as target material for dual-color, competitive hybridization to Agilent whole mouse genome 4x44K oligo arrays. All the significant targets found on the mircorarrays were compared against the various conditions to find a consensus of affected mir-146 mRNA targets.
2011-07-01 | E-GEOD-17759 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) are evolutionary conserved, non-coding, gene regulatory RNA molecules found in both plants and animals and amongst almost every cell and tissue type. They are about 22 nucleotides long and are involved in silencing of mRNA through sequence specific binding to the 3’ untranslated region (UTR) of the mRNA subsequently causing translational repression and/or will promote the degradation of protein-coding mRNA. Specifically, the miRNA family, mir-146 a/b, has been previously found to be involved in the regulation of the innate immune response by functioning as a negative regulator to help fine-tune the immune response. Microglial cells are the macrophage of the brain participating as major players of the innate immune response. During prion disease, no immune response is mounted against PrPSc possibly due to its similarity to host PrPc and thus, the host immune response would be suppressed and tightly regulated. Therefore, an increased expression of mir-146 by microglial cells during prion disease may function as one of these negative regulators. Our objective of this experiment is to use DNA microarrays to investigate the gene regulation of mir-146 previously found upregulated in our studies of mouse brain tissue specifically in microglial cells during prion disease with the aim of having a better understanding of prion pathobiology and a potential target for therapeutic intervention.
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