Role for MicroRNAs in Regulating Glucocorticoid Response and Resistance in Multiple Myeloma

Tessel, Michael A.; Benham, Ashley; Krett, Nancy L.; Rosen, Steven T.; Gunaratne, Preethi H.

doi:10.1007/s12672-011-0072-8

Cited by 63 publications

(53 citation statements)

References 34 publications

(32 reference statements)

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“…Previously, it has been shown that miR-130b regulates the glucocorticoid receptor on protein level in multiple myeloma (Tessel et al, 2011). Furthermore, the glucocorticoid receptor has been shown to regulate the transcription of CAR (Pascussi et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

Inflammation-Associated MicroRNA-130b Down-Regulates Cytochrome P450 Activities and Directly Targets CYP2C9

et al. 2015

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Expression of genes involved in absorption, distribution, metabolism, and excretion (ADME) of drugs is impaired in pathophysiologic conditions such as cholestasis and inflammation. The mechanisms of ADME gene down-regulation remain unclear. In our previous study, strongly elevated levels of microRNAs (miRNA) miR-21, miR-34a, and miR-130b in cholestatic liver and of miR-21 and miR-130b during inflammation were observed. Using HepaRG cells, which retain many functional characteristics of human hepatocytes, we investigated the potential of these miRNAs to down-regulate ADME genes. Cells were transfected with the corresponding miRNA mimics, chemically modified double-stranded RNAs that mimic endogenous miRNAs, followed by mRNA profiling by quantitative reversetranscription polymerase chain reaction. Activities of six cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4) were determined with a liquid chromatography with tandem mass spectrometric cocktail assay. Although miR-21 and miR-34a showed few effects, transfection of miR-130b led to significantly lower expression of nuclear receptors constitutive androstane receptor (CAR) and farnesoid X receptor (FXRa), the CYPs 1A1, 1A2, 2A6, 2C8, 2C9, and 2C19, as well as GSTA2. Furthermore, miR-130b negatively affected activity levels of all measured P450s by at least 30%. Reporter gene assays employing the CYP2C9 39-untranslated region (39-UTR) confirmed direct regulation by miR-130b. These data support miR-130b as a potential negative regulator of drug metabolism by directly and/or indirectly affecting the expression of several ADME genes. This may be of relevance in pathophysiologic conditions such as cholestasis and inflammation, which are associated with increased miR-130b expression.

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Section: Resultsmentioning

confidence: 99%

Inflammation-Associated MicroRNA-130b Down-Regulates Cytochrome P450 Activities and Directly Targets CYP2C9

et al. 2015

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“…Levels of GR may also be influenced by miRNA. In multiple myeloma cells, miR-130b inhibits GR and protein expression (29). Hydrocortisone-induction of miR-124 expression in lymphocytes is associated with the downregulation of the GR alpha (30).…”

Section: Discussionmentioning

confidence: 99%

Temporal Changes in Microrna Expression in Blood Leukocytes from Patients with the Acute Respiratory Distress Syndrome

Narute

Seam

Tropea

et al. 2017

Shock

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Background MicroRNA (miRNA) control gene transcription by binding to and repressing the translation of messenger RNA (mRNA). Their role in the acute respiratory distress syndrome (ARDS) is undefined. Methods Blood leukocytes from 51 patients enrolled in a prior randomized trial of corticosteroids for ARDS were analyzed. After screening eight patients with microarrays for altered miRNA expression, 25 miRNAs were selected for further analysis using RT-PCR in all 51 patients. Results On day 0, the 51 patients had APACHE III score of 60.4 ± 17.7 and PaO2/FiO2 of 117 ± 49. 21 miRNA were expressed at increased levels in blood leukocytes at the onset of ARDS compared to healthy controls. These miRNA remained elevated at day 3 and increased further by day 7 (log2 fold change from 0.66 to 5.7 fold, p <0.05 compared to day 0). In a subgroup analysis (37 patients treated with corticosteroids and 14 treated with placebo), the interaction of miRNA expression over time and steroid administration was not significant suggesting that systemic corticosteroids had no effect on the miRNA detected in our study. In contrast, corticosteroids but not placebo decreased IL-6 and C-reactive protein at day 3 (p<0.001) demonstrating an early systemic anti-inflammatory response whereas both treatment arms had decreased values by day 7 (p<0.001). Conclusions Expression of miRNA are increased in blood leukocytes of patients with ARDS at day 0 and day 3 and rise further by day 7, when systemic inflammation is subsiding. These effects appear independent of the administration of steroids, suggesting different inflammatory modifying roles for each in the resolving phases of ARDS.

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“…It was found that miR-124 specifi cally downregulated GR-α, and a slight increase of miR-124 and a reduction of GR-α were observed in patient T cells compared with healthy controls [ 108 ]. In addition, Tessel and colleagues [ 109 ] identifi ed and characterized miR-130b as an important downregulator of GR in a GC-resistant multiple myeloma cell line: The overexpression of this miRNA was also associated with a decreased regulation of GILZ , a downstream GC-controlled gene (Table 2 ).…”

Section: Mirnas Involved In Gr Regulation and Their Potential Rolementioning

confidence: 97%

Glucocorticoids in Pediatric Gastrointestinal Disorders

Iudicibus

Martelossi

Decorti

2015

Systemic Corticosteroids for Inflammatory Disorders in Pediatrics

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Pediatric Inflammatory Bowel Disease\ud Inflammatory bowel diseases (IBDs) are the most frequent chronic gastrointestinal disorders in pediatric age. They include two disease entities – Crohn’s disease (CD) and ulcerative colitis (UC) – which, although different in their pathogenesis, show common clinical characteristics such as chronic inflammation at different levels of the gastrointestinal tract and alternation between active and inactive phases. The incidence of IBD is increasing in recent years, particularly among children and adolescents, and it is currently estimated that 20–30 % of patients with IBD experience the onset of symptoms when they are under 20 years of age [1–3]. In childhood, IBDs are gener- ally more extended, more severe, and progress more rapidly than in adulthood. Moreover, therapy in children with IBD is more aggressive than in adults: Indeed, about 80 % of children need steroids, and about 30 % are subjected to an intestinal resection during a 5-year follow-up. Quality of life is severely affected in IBD, espe- cially for pediatric patients, owing to the chronic character of the disease that implies frequent hospitalizations and aggressive therapies, with a significant risk of side effects and a considerable impact on health care costs. IBD can result in loss of education and difficulty in gaining employment or insurance; overall, 15 % of patients with IBD are unable to work after 5–10 years of disease. Depressive disorders and low social func- tioning are also common among these patients, and the disease can also cause growth failure or retarded sexual development in young people [4–7]. It was recently reported that the mean individual annual costs in European countries amount to US$6,000 for CD and $4,600 for UC, and pediatric cases cost even more than adult ones [8]

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Role for MicroRNAs in Regulating Glucocorticoid Response and Resistance in Multiple Myeloma

Cited by 63 publications

References 34 publications

Inflammation-Associated MicroRNA-130b Down-Regulates Cytochrome P450 Activities and Directly Targets CYP2C9

Inflammation-Associated MicroRNA-130b Down-Regulates Cytochrome P450 Activities and Directly Targets CYP2C9

Temporal Changes in Microrna Expression in Blood Leukocytes from Patients with the Acute Respiratory Distress Syndrome

Glucocorticoids in Pediatric Gastrointestinal Disorders

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