Small RNA profiling reveals deregulated phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/Akt pathway in bronchial smooth muscle cells from asthmatic patients

Alexandrova, Elena; Miglino, Nicola; Hashim, Adnan; Nassa, Giovanni; Stellato, Claudia; Tamm, Michael; Baty, Florence; Brutsche, Martin; Weisz, Alessandro; Borger, Pieter

doi:10.1016/j.jaci.2015.05.031

Cited by 32 publications

(24 citation statements)

References 69 publications

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“…As observed for the CMC signatures, the pathway activation data (heatmap, Figure 2A ) also clearly distinguished between BSM cells of asthmatic and non-asthmatic subjects. In accord with our previous studies analysing small noncoding RNA expression patterns [ 21 ], the PTEN/AKT signalling system was again amongst the most affected ISPs.…”

Section: Discussionsupporting

confidence: 89%

“…We have hypothesized and provided evidence that the “primed” phenotype of asthmatic BSM cells is reflected in the signalling pathway signature of the cells. Using small RNA profiling we recently identified deregulated phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/Akt pathways in BSM cells of asthmatic patients as a candidate for a primed phenotype [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Large-scale profiling of signalling pathways reveals an asthma specific signature in bronchial smooth muscle cells

et al. 2016

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BackgroundBronchial smooth muscle (BSM) cells from asthmatic patients maintain in vitro a distinct hyper-reactive (“primed”) phenotype, characterized by increased release of pro-inflammatory factors and mediators, as well as hyperplasia and/or hypertrophy. This “primed” phenotype helps to understand pathogenesis of asthma, as changes in BSM function are essential for manifestation of allergic and inflammatory responses and airway wall remodelling.ObjectiveTo identify signalling pathways in cultured primary BSMs of asthma patients and non-asthmatic subjects by genome wide profiling of differentially expressed mRNAs and activated intracellular signalling pathways (ISPs).MethodsTranscriptome profiling by cap-analysis-of-gene-expression (CAGE), which permits selection of preferentially capped mRNAs most likely to be translated into proteins, was performed in human BSM cells from asthmatic (n=8) and non-asthmatic (n=6) subjects and OncoFinder tool were then exploited for identification of ISP deregulations.ResultsCAGE revealed >600 RNAs differentially expressed in asthma vs control cells (p≤0.005), with asthma samples showing a high degree of similarity among them. Comprehensive ISP activation analysis revealed that among 269 pathways analysed, 145 (p<0.05) or 103 (p<0.01) are differentially active in asthma, with profiles that clearly characterize BSM cells of asthmatic individuals. Notably, we identified 7 clusters of coherently acting pathways functionally related to the disease, with ISPs down-regulated in asthma mostly targeting cell death-promoting pathways and up-regulated ones affecting cell growth and proliferation, inflammatory response, control of smooth muscle contraction and hypoxia-related signalization.ConclusionsThese first-time results can now be exploited toward development of novel therapeutic strategies targeting ISP signatures linked to asthma pathophysiology.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Large-scale profiling of signalling pathways reveals an asthma specific signature in bronchial smooth muscle cells

et al. 2016

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“…Here, 1 µg of each FFPE-or cell line-derived sample was used for sequencing library preparation using TruSeq Small RNA kit (Illumina Inc., San Diego, CA, USA) as previously described [26]. Each library was sequenced on HiSeq 2500 (Illumina Inc., San Diego, CA, USA) at a concentration of 10 pM for 50 cycles plus seven additional cycles for index sequencing in the single-read mode (1 × 50 base pairs).…”

Section: Sncrna Sequencing and Data Analysismentioning

confidence: 99%

“…As highly predicted miRNA targets, we considered only mRNAs characterized by a prediction score equal to 1 and identified by at least two out of four algorithms present in miRWalk database. For cell lines, differentially expressed mRNAs with |FC| ≥ 1.5 were considered as putative miRNA targets, taking into account both experimentally validated and highly predicted interactions, as done in our previous paper [26]. For the prediction of miRNA targets in TNBC tissues, publicly available RNA-seq data from the TCGA Breast Cancer dataset [25] were downloaded and all predicted miRNA-targeted RNAs were identified and taken into account, excluding transcripts that were not expressed in the tissues.…”

Section: Sncrna Sequencing and Data Analysismentioning

confidence: 99%

Small Non-Coding RNA Profiling Identifies miR-181a-5p as a Mediator of Estrogen Receptor Beta-Induced Inhibition of Cholesterol Biosynthesis in Triple-Negative Breast Cancer

Alexandrova

Lamberti

Saggese

et al. 2020

Cells

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Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, representing the most aggressive breast cancer (BC) subtype with limited treatment options due to a lack of estrogen receptor alpha (ERα), progesterone receptor (PR), and Erb-B2 receptor tyrosine kinase 2 (HER2/neu) expression. Estrogen receptor beta (ERβ) is present in a fraction of TNBC patients, where its expression correlates with improved patient outcomes, supported by the fact that it exerts oncosuppressive effects in TNBC cell models in vitro. ERβ is involved in microRNA-mediated regulation of gene expression in hormone-responsive BC cells and could mediate its actions through small noncoding RNAs (sncRNAs) in TNBCs also. To verify this possibility, smallRNA sequencing was performed on three ERβ-expressing cell lines from different TNBC molecular subtypes. Several sncRNAs resulted modulated by ERβ, with a subset being regulated in a tumor subtype-independent manner. Interestingly, sncRNA profiling of 12 ERβ+and 32 ERβ− primary TNBC biopsies identified 7 microRNAs, 1 PIWI-interacting RNA (piRNA), and 1 transfer RNA (tRNA) differentially expressed in ERβ+ compared to ERβ− tumors and cell lines. Among them, miR-181a-5p was found to be overexpressed in ERβ+ tumors and predicted target key components of the cholesterol biosynthesis pathway previously found to be inhibited by ERβ in TNBC cells.

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“…A large majority of these remain uncorrected or modestly corrected despite treatment with steroids [ 71 ]. Another recent study revealed that about 26 miRNAs are aberrantly expressed in the bronchial smooth muscle cells of asthmatic cells [ 72 ]. Besides, the target mRNAs of these aberrantly regulated miRNAs were found to play important roles in asthma pathogenesis in the form of cellular proliferation through phosphatase and tensin homolog and phosphoinositide 3-kinase/Akt signaling pathways.…”

Section: Epigenetic Mechanisms In Asthma: the Means To An Endmentioning

confidence: 99%

Epigenetics: The New Frontier in the Landscape of Asthma

Bhattacharjee

Chogtu

2016

Scientifica

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Over the years, on a global scale, asthma has continued to remain one of the leading causes of morbidity, irrespective of age, sex, or social bearings. This is despite the prevalence of varied therapeutic options to counter the pathogenesis of asthma. Asthma, as a disease per se, is a very complex one. Scientists all over the world have been trying to obtain a lucid understanding of the machinations behind asthma. This has led to many theories and conjectures. However, none of the scientific disciplines have been able to provide the missing links in the chain of asthma pathogenesis. This was until epigenetics stepped into the picture. Though epigenetic research in asthma is in its nascent stages, it has led to very exciting results, especially with regard to explaining the massive influence of environment on development of asthma and its varied phenotypes. However, there remains a lot of work to be done, especially with regard to understanding how the interactions between immune system, epigenome, and environment lead to asthma. But introduction of epigenetics has infused a fresh lease of life in research into asthma and the mood among the scientific community is that of cautious optimism.

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Small RNA profiling reveals deregulated phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/Akt pathway in bronchial smooth muscle cells from asthmatic patients

Abstract: BSM cells of asthmatic patients are characterized by aberrant sncRNA expression that recapitulates multiple pathologic phenotypes of these cells.

Cited by 32 publications

References 69 publications

Large-scale profiling of signalling pathways reveals an asthma specific signature in bronchial smooth muscle cells

Large-scale profiling of signalling pathways reveals an asthma specific signature in bronchial smooth muscle cells

Small Non-Coding RNA Profiling Identifies miR-181a-5p as a Mediator of Estrogen Receptor Beta-Induced Inhibition of Cholesterol Biosynthesis in Triple-Negative Breast Cancer

Epigenetics: The New Frontier in the Landscape of Asthma

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