The HER2-Encoded miR-4728-3p Regulates ESR1 through a Non-Canonical Internal Seed Interaction

Newie, Inga; Søkilde, Rolf; Persson, Helena; Grabau, Dorthe; Rego, Natalia; Kvist, Anders; Stedingk, Kristoffer von; Axelson, Håkan; Borg, Åke; Vallon‐Christersson, Johan; Rovira, Carlos

doi:10.1371/journal.pone.0097200

Cited by 27 publications

(30 citation statements)

References 38 publications

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“…For the first batch, the most enriched motifs among downregulated genes corresponded to targets of hsa-miR-4728-3p, as expected (compare Newie et al 5 and Fig. 1A).…”

Section: Resultssupporting

confidence: 84%

“…During functional studies of the miRNA hsa-miR-4728-3p 5 we used several batches of the same commercially available miRNA mimic in overexpression studies in cell culture. To determine the target genes for this miRNA, we also performed microarray expression analysis and searched for differential expression between cells transfected with an hsa-miR-4728-3p mimic or a non-targeting control mimic.…”

Section: Resultsmentioning

confidence: 99%

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Passenger strand loading in overexpression experiments using microRNA mimics

et al. 2015

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MicroRNAs (miRNAs) are important regulators of gene function and manipulation of miRNAs is a central component of basic research. Modulation of gene expression by miRNA gain-of-function can be based on different approaches including transfection with miRNA mimics; artificial, chemically modified miRNA-like small RNAs. These molecules are intended to mimic the function of a miRNA guide strand while bypassing the maturation steps of endogenous miRNAs. Due to easy accessibility through commercial providers this approach has gained popularity, and accuracy is often assumed without prior independent testing. Our in silico analysis of over-represented sequence motifs in microarray expression data and sequencing of AGO-associated small RNAs indicate, however, that miRNA mimics may be associated with considerable side-effects due to the unwanted activity of the miRNA mimic complementary strand.

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“…For the first batch, the most enriched motifs among downregulated genes corresponded to targets of hsa-miR-4728-3p, as expected (compare Newie et al 5 and Fig. 1A).…”

Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Passenger strand loading in overexpression experiments using microRNA mimics

et al. 2015

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“…MIR4728 gene is located at chr17q12 and encoded within intron 24 of the ERBB2 gene (43). Recently, Newie and colleagues demonstrated that ERBB2 amplification might lead to ESR1 downregulation through internal seed interaction with miR-4728-3p in breast cancer cells (44). We corroborate this observation identifying a positive correlation between ERBB2 and MIR4728 expression ( r = 0.90; P < 0.01) in DCIS samples in agreement with the CNV data.…”

Section: Resultsmentioning

confidence: 99%

A Molecular Portrait of High-Grade Ductal Carcinoma In Situ

et al. 2015

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Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.

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“…To this extent, Shin et al noticed a decreased expression of miR-16, miR-21 and miR-199a-5p along with an increase in the levels of miR-92a-3p and miR-342-3p in both blood and tissue samples collected from TNBC patients [188]. Meanwhile, in HER2+ tumors, it has repeatedly been shown that miR-4728 is co-expressed with HER2, acting as an oncogene [189][190][191]. Moreover, Søkilde et al have recently demonstrated the expression of two other small RNAs in HER2-enriched tumors, namely miR-2115 and miR-7158, which are otherwise very lowly expressed in healthy tissues [192].…”

Section: Mirnas In Distinguishing Cancer Subtypesmentioning

confidence: 99%

miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis

Condrat

Thompson

Barbu

et al. 2020

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MicroRNAs (miRNAs) represent a class of small, non-coding RNAs with the main roles of regulating mRNA through its degradation and adjusting protein levels. In recent years, extraordinary progress has been made in terms of identifying the origin and exact functions of miRNA, focusing on their potential use in both the research and the clinical field. This review aims at improving the current understanding of these molecules and their applicability in the medical field. A thorough analysis of the literature consulting resources available in online databases such as NCBI, PubMed, Medline, ScienceDirect, and UpToDate was performed. There is promising evidence that in spite of the lack of standardized protocols regarding the use of miRNAs in current clinical practice, they constitute a reliable tool for future use. These molecules meet most of the required criteria for being an ideal biomarker, such as accessibility, high specificity, and sensitivity. Despite present limitations, miRNAs as biomarkers for various conditions remain an impressive research field. As current techniques evolve, we anticipate that miRNAs will become a routine approach in the development of personalized patient profiles, thus permitting more specific therapeutic interventions.Biogenesis of miRNA begins in the nucleus, where the transcription of its precursor, primary miRNA or pri-miRNA takes place under the influence of RNA polymerases II and III [11,12]. The resulting molecule is a hairpin-like structure, which contains a loop at one end [11]. This primordial mi-RNA precursor that is usually made up of hundreds of nucleotides is then processed consecutively by two RNase III enzymes [13][14][15]. The first enzyme to act upon the pri-miRNA, which still resides in the nucleus, is called Drosha or DCGR8, and turns it into a new hairpin-like structure of approximately 70 nucleotides, the Precursor-miRNA or pre-miRNA. The latter is then transported to the cytoplasm, with the help of Exportin-5, where it is cleaved again by the Ago2/Dicer complex leading to the short, mature miRNA double strands [16].Further on, one of the strands, usually known as the guide strand, will be integrated into the RNA-induced silencing complex (RISC), while the other one, known as the passenger strand, is going to be degraded, even though in some occasions it has been found to be also functional [17]. In most cases, the strand that contains the less stable 5 end or a uracil at the beginning is more likely to be selected as the guide strand [18][19][20]. In those situations, where the passenger strand is not degraded and both get incorporated into the miRISC complex, the mature miRNA in the guide strand will be the dominant one [21,22].The main role of miRNA in the human body is gene regulation [23] by mediating the degradation of mRNA and also by regulating transcription and translation through canonical and non-canonical mechanisms [4]. The canonical mechanism means that the miRISC complex containing the miRNA guide strand is exerting its action by binding to the targ...

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The HER2-Encoded miR-4728-3p Regulates ESR1 through a Non-Canonical Internal Seed Interaction

Cited by 27 publications

References 38 publications

Passenger strand loading in overexpression experiments using microRNA mimics

Passenger strand loading in overexpression experiments using microRNA mimics

A Molecular Portrait of High-Grade Ductal Carcinoma In Situ

miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis

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