Regulation and function of miRNA-21 in health and disease
Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.RNA biology (Impact Factor: 4.97). 09/2011; 8(5):706-13. DOI: 10.4161/rna.8.5.16154
The small regulatory RNA microRNA-21 (miR-21) plays a crucial role in a plethora of biological functions and diseases including development, cancer, cardiovascular diseases and inflammation. The gene coding for pri-miR-21 (primary transcript containing miR-21) is located within the intronic region of the TMEM49 gene. Despite pri-miR-21 and TMEM49 are overlapping genes in the same direction of transcription, pri-miR-21 is independently transcribed by its own promoter regions and terminated with its own poly(A) tail. After transcription, primiR- 21 is finally processed into mature miR-21. Expression of miR-21 has been found to be deregulated in almost all types of cancers and therefore was classified as an oncomiR. During recent years, additional roles of miR-21 in cardiovascular and pulmonary diseases, including cardiac and pulmonary fibrosis as well as myocardial infarction have been described. MiR-21 additionally regulates various immunological and developmental processes. Due to the critical functions of its target proteins in various signaling pathways, miR-21 has become an attractive target for genetic and pharmacological modulation in various disease conditions.
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[Show abstract] [Hide abstract] ABSTRACT: Tuberous sclerosis complex (TSC) is a genetic disease presenting with multiple neurological symptoms including epilepsy, mental retardation, and autism. Abnormal activation of various inflammatory pathways has been observed in astrocytes in brain lesions associated with TSC. Increasing evidence supports the involvement of microRNAs in the regulation of astrocyte-mediated inflammatory response. To study the role of inflammation-related microRNAs in TSC, we employed real-time PCR and in situ hybridization to characterize the expression of miR21, miR146a, and miR155 in TSC lesions (cortical tubers and subependymal giant cell astrocytomas, SEGAs). We observed an increased expression of miR21, miR146a, and miR155 in TSC tubers compared with control and perituberal brain tissue. Expression was localized in dysmorphic neurons, giant cells, and reactive astrocytes and positively correlated with IL-1β expression. In addition, cultured human astrocytes and SEGA-derived cell cultures were used to study the regulation of the expression of these miRNAs in response to the proinflammatory cytokine IL-1β and to evaluate the effects of overexpression or knockdown of miR21, miR146a, and miR155 on inflammatory signaling. IL-1β stimulation of cultured glial cells strongly induced intracellular miR21, miR146a, and miR155 expression, as well as miR146a extracellular release. IL-1β signaling was differentially modulated by overexpression of miR155 or miR146a, which resulted in pro- or anti-inflammatory effects, respectively. This study provides supportive evidence that inflammation-related microRNAs play a role in TSC. In particular, miR146a and miR155 appear to be key players in the regulation of astrocyte-mediated inflammatory response, with miR146a as most interesting anti-inflammatory therapeutic candidate. GLIA 2016.
- "Moreover, a positive correlation was observed between these miRNAs and IL-1b in both tumor and peritumoral cortex in GG (Prabowo et al., 2015) and in TSC specimens (miR21 and miR155, present data). Previous studies have shown that miR21 can be induced by NF-jB and may act as negative-feedback regulator of Tolllike receptor signaling via targeting of the pro-inflammatory tumor suppressor PDCD4 (He et al., 2014; Kumarswamy et al., 2011; O'Connell et al., 2012; O'Neill et al., 2011; Sheedy et al., 2010). In the present study, we confirmed the intracellular induction of this microRNA by IL-1b in both astrocytes and SEGA cells. "
[Show abstract] [Hide abstract] ABSTRACT: Intercellular signaling via exosomes is a burgeoning topic in biomedical research, now having been associated with a host of disease states. These nanosized, membrane-encapsulated vesicles shuttle biomolecules between cells, facilitating intercellular cross-talk. A major player among these biomolecules are microRNA (miRNA), which are a class of small non-coding RNA molecules that negatively regulate the expression of their target genes and therefore can impact the expression profile of recipient cells when transferred via exosomes. While evidence for the involvement of exosomal transfer of miRNA in various disease processes is rapidly mounting, research into the impact of the external environment on exosomal transfer of miRNA is slowly starting to emerge and represents an exciting new area of research. This review will summarize the current nascent state of the literature on the potential relationship between exosomal miRNA and the environment exposures and provide some potential considerations and directions for work in this field.
- "It can exist in several oxidation states through which it can combine with oxygen (O), chlorine (Cl), or sulfur (S) to form inorganic arsenic compounds, with arsenite (As III ) compounds considered to be the most toxic [45, 46]. Arsenite has been shown to upregulate miR-21 , an oncogenic miRNA that is commonly upregulated in a host of different cancer types . Although indirect, Xu and colleagues showed that arsenite-transformed malignant human bronchial epithelial (HBE) cells transferred exosomes containing miR-21 to nonneoplastic HBE cells in non-contact co-culture, resulting in the stimulation of proliferation , leading them to conclude that exosomal miR-21 may be involved in arsenite-induced malignant transformation. "
[Show abstract] [Hide abstract] ABSTRACT: Tachycardia-induced atrial fibrosis is a hallmark of the structural remodeling of atrial fibrillation (AF). The mechanisms underlying tachycardia-induced atrial fibrosis remain unclear. In our previous study, we found that Smad7-downregulation promoted the development of atrial fibrosis in AF. Fibroblasts are enriched in microRNA-21 (miR-21), which contributes to the development of fibrosis and heart failure in the cardiovascular system. Our study was designed to test the hypothesis that miR-21 reinforces the TGF-β1/Smad signaling pathway in AF-induced atrial fibrosis by down-regulating Smad7. Rapid atrial pacing (RAP, 1000 ppm) was applied to the left atrium of the rabbit heart to induce atrial fibrillation and fibrosis. qRT-PCR and northern blot analysis revealed that RAP caused a marked increase in the expression of miR-21. Transfection with a miR-21 inhibitor significantly increased the expression of Smad7, while the expression of collagen I/III significantly decreased. These changes were implicated in the AF-induced release of miR-21 and down-regulation of Smad7. Adult rat cardiac fibroblasts treated with TGF-β1 showed increased miR-21 expression and decreased Smad7 expression. Pretreatment with a TGF-β1 inhibitor reduced the TGF-β1-induced up-regulation of miR-21. Pretreatment with pre-miR-21 and a miR-21 inhibitor significantly decreased and increased Smad7 expression, respectively. This result was negatively correlated with the expression of collagen I/III in fibroblasts. Moreover, the results of a luciferase activity assay suggest that Smad7 is a validated miR-21 target in CFs. Our results provide compelling evidence that the miR-21 specific degradation of Smad7 may decrease the inhibitory feedback regulation of TGF-β1/Smad signaling and serves as a new insight of the mechanism of atrial fibrosis in atrial fibrillation.
- "Earlier reports have shown that miR-21 is extensively involved in myocardial fibrosis, and miR-21 is considered to be associated with TGF-β 1 -induced myocardial fibrosis [22, 32]. However, there are few reports about the role of miR-21 in AF. "