MiRNA 21 is a mammalian micro RNA that is encoded by the MIR21 gene. The primary transcript of the gene is cut by the endonuclease Drosha in the nucleus and, after being transported in the cytosol, is cut in to a short RNA duplex by Dicer.Only one of this two strand is going to become a mature miRNA, while the other is going to be degraded, due to the thermodinamic stability of each end of the duplex ( Identification of novel genes coding for small expressed RNAs, 2001 )
Mir21 is the first mirna to be described as an “oncomir”. A most of its targets are tumor suppressors, it is associated with a wide variety of cancer. Here some of the more recent studies about its function and its possible feature to become a biomarker for some pathologies.
Mir 21 Expression.
Human mir21 is located in an intron of the protein coding gene TMEM49. Analysis of the consensus sequences within the miR-21 promoter region identified several conserved enhancer elements, including binding sites for AP-1 ( composed of Fos and Jun family nuclear oncogenes ), ts/PU.1, C/EBP-α (both key factors governing hematopoietic lineage differentiation), nuclear factor I (NFI), SRF, p53 and STAT3.
Overexpression of miR-21 has been reported in many malignancies, all of which contain constitutively activated STAT3, or even rely on STAT3 with respect to cell survival or growth. Mir21 expression is negatively regulated by IFN-β through STAT3 activation, supporting the hypothesis that STAT3 activation exerts a cytostatic or anti-proliferative effect in some types of cells. The possible explanation for the seemingly paradoxical role of STAT3 activation is that the STAT pathway is context-dependent. This discrepancy may arise from differences
in cytokine stimulus and cell type.
Furthermore, the NFI-B protein usually binds to the miR-21 promoter and acts as a negative regulator; thus, there is a double-negative feedback mechanism operating between miR-21 and NFIB, which sustains miR-21 expression.
Programmed cell death protein 4 (PDCD4), a direct target of miR-21 in both solid tumors and hematological malignancies, is a negative regulator of AP-1 ( which is a mir21 activator ). Activation of miR-21 by AP-1 in response to RAS oncoprotein downregulated the expression of its
target gene, PDCD4, which in turn contributed to the increase in AP-1 activity and thyroid cell viability.
MiR-21 is also significantly activated in human biliary epithelial cells induced by LPS via binding of the NFκB subunit, p65, to the promoter elements of pri-miR-21, suggesting a role for NFκB in the regulation of miRNA genes.
In addition TGF-β may upregulate miR-21 expression in vascular smooth muscle cells identified additional mechanisms that control miR-21 processing which, again, make this molecule extremely interesting ( MicroRNA-21: a novel therapeutic target in human cancer, 2009 ).
Mir 21 and cancer
In 2005 an Italian research group found a potent association between mir21 and breast cancer:
miR-21 is progressively up-regulated from normal breast to cancers with high tumor stage. These finding suggest that deregulation of this miRNA may affect critical molecular events involved in tumor progression ( MicroRNA gene expression deregulation in human breast cancer, 2005 ).
One more evidence that mirna 21 (and generally microRNA) is involved in the pathogenesis of solid tumor is given by another Italian group ( A microRNA expression signature of human solid tumors defines cancer gene targets, 2006 ). Troughout this study the authors found a differential expression statistically significative in normal cell versus lung-cancer cells of several miRNA including mir21.
MiRNA 21 is beside involved in brain cancer, in particular Glioblastoma ( MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells, 2005 ). In six glioblastoma cell-lines the authors found a huge over-expression of miRNA 21 compared to non neoplastic fetal and adult brain cell-lines. Plus it is confirmed it is possible to trigger the caspase dependet apopthotic pathway in tumor cell-lines by knoking out the miRNA 21 gene.
Meng et.al ( MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer,2007 ) in 2007 found that mir21 regulates the expression of the PTEN tumor suppressor gene in huma hepatocellular cancer. Inhibition of miR-21 in cultured HCC cells increased expression of the phosphatase and tensin homolog (PTEN) tumor suppressor, and decreased tumor cell proliferation, migration, and invasion. In contrast-enhanced miR-21 expression by transfection with precursor miR-21 increased tumor cell proliferation, migration, and invasion. Moreover, an increase in cell migration was observed in normal human hepatocytes transfected with precursor miR-21. PTEN was shown to be a direct target of miR-21, and to contribute to miR-21 effects on cell invasion.
Mir21 and Heart Disease
Mir 21 has been shown to play an important role in development of hearth disease.
microRNA-21 regulates the ERK-MAP kinase signalling pathway in cardiac fibroblasts, which has impacts on global cardiac structure and function. miR-21 levels are increased selectively in fibroblasts of the failing heart, augmenting ERK-MAP kinase activity through inhibition of sprouty homologue 1 (Spry1). This mechanism regulates fibroblast survival and growth factor secretion, apparently controlling the extent of interstitial fibrosis and cardiac hypertrophy. In vivo silencing of miR-21 by a specific antagomir in a mouse pressure-overload-induced disease model reduces cardiac ERK-MAP kinase activity, inhibits interstitial fibrosis and attenuates cardiac dysfunction ( MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts, 2008 ).
In 2009 a study revealed how overexpression of miR-21 via adenovirus expressing miR-21 decreased myocardial infarct size by 29% at 24 h and decreased the dimension of left ventricles at 2 weeks after Acute Myocardical Infarction ( MicroRNA Expression Signature and the Role of MicroRNA-21 in the Early Phase of Acute Myocardial Infarction,2009 ).
Mir21 and Kidney
Recent studies revealed that mir21 has a strong role in several kidney disease. In 2012 Szeto et.al (Micro-RNA expression in the urinary sediment of patients with chronic kidney diseases, 2012 ) after quantification of urinary miRNA levels in a popolation of 56 patients with cronic kidney disease, revealed that the rate of renal function decline correlated with urinary expression of miR-21 and other miRNAs. Patients with a high urinary expression of miR-21 had better dialysis-free survival than those with low expression.
Similarly another study confirm that high mir21 levels, acquired trough RT-qPCR of urinary sediment, in patient with AKI were associated with the progression of the disease. Furthermore these datas predicted the need of postoperative renal replacement therapy ( MicroRNA-21 and risk of severe acute kidney injury and poor outcomes after adult cardiac surgery, 2013 ).
Mir21 as a novel biomarker
The summa of this datas suggest that further studies could confirm mir21 as a novel biomarker for prediction several patologies, which is particularly important for kidney disease, delayed graft function, acute and cronich kidney injury, and generally for some type of carcinomas (being mir 21 an “oncomir”) ( Urinary miR-21, miR-29, and miR-93: novel biomarkers of fibrosis, 2009 ).
Mir 21 can be for example a biomarker for the Renal Cell Carcinoma: higher level of mir21 correlates with higher stage and grade of RCC. Furthermore its expression could be diagnostically significative in distinguishing many RCC subtypes ( The clinical utility of miR-21 as a diagnostic and prognostic marker for renal cell carcinoma, 2012 ).