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The HER2-encoded miR-4728-3p regulates ESR1 through a non-canonical internal seed interaction

ABSTRACT: Since the early 1980s remarkable progress has been made in understanding the role of the HER2 locus in carcinogenesis, but many details of its regulatory network are still elusive. We recently reported the finding of 367 new human microRNA (miRNA) genes of which one, mir-4728, is encoded in an intron of the HER2 gene. Here, we confirm that the HER2 oncogene is a bi-functional locus encoding the membrane receptor and a functional miRNA gene. We further show that miR-4728-3p has alternative functionalities depending on the region used for interaction with its target; the canonical seed between nucleotides 2-8 or a novel, more internal seed shifted to nucleotides 6-12. Analysis of public data shows that this internal seed region, although rare compared to the far more abundant canonical 2-8 seed interaction, can also direct targeted down-regulation by other miRNAs. Through the internal seed, miR-4728-3p regulates expression of estrogen receptor alpha, an interaction that would have remained undetected if classic rules for miRNA-target interaction had been applied. In summary, we present here an alternative mode of miRNA regulation and demonstrate this dual function of the HER2 locus, linking the two major biomarkers in breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55822 | GEO | 2014/08/13

SECONDARY ACCESSION(S): PRJNA241075

REPOSITORIES: GEO

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The HER2-encoded miR-4728-3p regulates ESR1 through a non-canonical internal seed interaction

Project description:Since the early 1980s remarkable progress has been made in understanding the role of the HER2 locus in carcinogenesis, but many details of its regulatory network are still elusive. We recently reported the finding of 367 new human microRNA (miRNA) genes of which one, mir-4728, is encoded in an intron of the HER2 gene. Here, we confirm that the HER2 oncogene is a bi-functional locus encoding the membrane receptor and a functional miRNA gene. We further show that miR-4728-3p has alternative functionalities depending on the region used for interaction with its target; the canonical seed between nucleotides 2-8 or a novel, more internal seed shifted to nucleotides 6-12. Analysis of public data shows that this internal seed region, although rare compared to the far more abundant canonical 2-8 seed interaction, can also direct targeted down-regulation by other miRNAs. Through the internal seed, miR-4728-3p regulates expression of estrogen receptor alpha, an interaction that would have remained undetected if classic rules for miRNA-target interaction had been applied. In summary, we present here an alternative mode of miRNA regulation and demonstrate this dual function of the HER2 locus, linking the two major biomarkers in breast cancer. 6 samples treated with hsa-miR-4728-3p mimic and 6 samples treated with non-targeting control 4 samples treated with hsa-miR-1-3p mimic and 4 samples treated with non-targeting control

2014-08-13 | E-GEOD-55822 | biostudies-arrayexpress

Homo sapiens

Project description:The HER2-encoded miR-4728-3p regulates ESR1 through a non-canonical internal seed interaction

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miRNA profiling in camptothecin-treated or untreated hepatoma-derived exosomes

Project description:Totally 1,308 miRNAs were examined. Three miRNAs (hsa-miR-1976, 4728-3p, and 877-3p) were upregulated with fold change excess 0.8 and six miRNAs (hsa-miR-4497, -204-3p, -6126, -5787, -1273e, and -1908-3p) were downregulated in the exosome released from camptothecin-treated hepatoma. Comparing between results of these two samples revealed novel miRNA regulation upon anti-cancer drug treatments exosomal miRNAs from CPT-treated hepatoma and unrteated

2015-11-10 | E-GEOD-74829 | biostudies-arrayexpress

MicroRNA in combination with HER2-targeting drugs reduces breast cancer cell viability in vitro

Project description:HER2-positive (HER2+) breast cancer patients that do not respond to targeted treatment have a poor prognosis. The effects of targeted treatment on endogenous microRNA (miRNA) expression levels are unclear. We report that responsive HER2+ breast cancer cell lines had a higher number of miRNAs with altered expression after treatment with trastuzumab and lapatinib compared to poorly responsive cell lines. To evaluate whether miRNAs can sensitize HER2+ cells to treatment, we performed a high-throughput screen of 1626 miRNA mimics and inhibitors in combination with trastuzumab and lapatinib in HER2+ breast cancer cells. We identified eight miRNA mimics sensitizing cells to targeted treatment, miR-101-5p, mir-518a-5p, miR-19b-2-5p, miR-1237-3p, miR-29a-3p, miR-29c-3p, miR-106a-5p, and miR-744-3p. A higher expression of miR-101-5p predicted better prognosis in patients with HER2+ breast cancer (OS: p=0.0392; BCSS: p=0.0125), supporting the tumor-suppressing role of this miRNA. In conclusion, we have identified miRNAs that sensitize HER2+ breast cancer cells to targeted therapy. This indicates the potential of combining targeted drugs with miRNAs to improve current treatments for HER2+ breast cancers.

2021-05-21 | GSE163490 | GEO

miRNA profiling in camptothecin-treated or untreated hepatoma-derived exosomes

2015-11-10 | GSE74829 | GEO

Rapid decay of engulfed extracellular miRNA by XRN1 exonuclease promotes transient epithelial-mesenchymal transition

Project description:To analyze the effect of miR-223-3p expression on the mRNA level we employed whole genome microarray expression profiling to identify genes with a potential seed region targeted by miR-223-3p. A549 cells were transfected for 48h with either a mirVana miRNA mimic Control or miR-223-3p.

2017-01-25 | GSE81370 | GEO

microRNA-seq of cartilage reveals an over-abundance of miR-140-3p which contains functional isomiRs (Illumina HT12v4 expression arrays)

Project description:MiR-140 is selectively expressed in cartilage. Deletion of the entire miR-140 locus in mice results in a growth retardation phenotype and an early-onset osteoarthritis-like pathology, however the relative contribution of miR-140-5p or miR-140-3p to the phenotype remains to be determined. An unbiased small RNA sequencing approach identified that miR-140-3p was in vast abundance (>10-fold) to miR-140-5p in human cartilage. Analysis of these data identified multiple miR-140-3p isomiRs differing from the miRBase [1] annotation at both the 5´ and 3´ end, with >99% of miR-140-3p isomiRs having one of two ‘seed’ sequences (5´ bases 2-8). The most abundant isomiR with each seed were selected for further analysis; miR-140-3p.2 which has an identical seed to the miRBase miR-140-3p (ACCACAG) and miR-140-3p.1 which has an altered seed (CCACAGG), and thus different potential targets. Each isomiR was overexpressed in chondrocytes and whole-genome transcriptomics used to identify targets. miR-140-3p.1 and miR-140-3p.2 significantly down-regulated 694 and 238 genes respectively (adj.P.Val<0.05), of which only 162 genes were commonly down-regulated by both isomiRs. Targets of both isomiRs were validated using 3´UTR luciferase assays. A significant enrichment of miR-140-3p.1 targets was identified within genes whose expression increase in the rib chondrocytes of Mir140-null mice and within genes whose expression decreased during human chondrogenesis. Finally, through imputing the expression of miR-140 from the expression of the host gene WWP2 in 124 previously published datasets an inverse correlation with miR-140-3p.1 predicted targets was identified. Together these data suggest the novel seed containing isomiR miR-140-3p.1 is more functional than the original consensus miR-140-3p or the isomiR with the same seed, miR-140-3p.2.

2020-07-17 | GSE144367 | GEO

5b763f6e-2031-4d46-913d-ee7491e7e50c - samples

Project description:iPSC-derived neurons were treated with mimics and inhibitors of the miRNAs miR-150-5p, hsa-mir-193a-3p and hsa-miR-19b-3p. RNA-sequencing was then performed to examine the effects of miRNA up-regulation and inhibition.

| EGAD00001006844 | EGA

Refinement of breast cancer molecular classification by miRNA expression profiles

Project description:Background: Accurate classification of breast cancer using gene expression profiles has contributed to a better understanding of the biological mechanisms behind the disease and has paved the way for better prognostication and treatment prediction. Results: We found that miRNA profiles largely recapitulate intrinsic subtypes. In the case of HER2-enriched tumors a small set of miRNAs including the HER2-encoded mir-4728 identifies the group with very high specificity. We also identified differential expression of the miR-99a/let-7c/miR-125b miRNA cluster as a marker for separation of the Luminal A and B subtypes. High expression of this miRNA cluster is linked to better overall survival among patients with Luminal A tumors. Correlation between the miRNA cluster and their precursor LINC00478 is highly significant suggesting that its expression could help improve the accuracy of present day’s signatures. Conclusions: We show here that miRNA expression can be translated into mRNA profiles and that the inclusion of miRNA information facilitates the molecular diagnosis of specific subtypes, in particular the clinically relevant sub-classification of luminal tumors.

2019-06-20 | GSE131599 | GEO

Identification of miR-16/29 targets in adipocytes by LC-MSMS

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