MIRN21

Gene

MIRN21 was one of the first mammalian microRNAs identified. The human microRNA-21 gene is located on the plus strand of chromosome 17q23.2 (55273409–55273480), within the coding gene TMEM49 (also known as vacuole membrane protein). Although it resides within the intronic region of this gene and shares the same direction of transcription, miR-21 has its own promoter regions and is independently transcribed. Its primary transcript (pri-miR-21) is approximately 3433 nucleotides in length. The precursor stem–loop structure of miR-21 (pre-miR-21) is located between nucleotides 2445 and 2516 of pri-miR-21.

Structure

Pri-miR-21 is initially processed in the nucleus by the endonuclease Drosha, which cleaves it into the precursor form, pre-miR-21. This precursor is then exported into the cytosol, where it is further cleaved by the enzyme Dicer into a short RNA duplex. Although both strands are transcribed in equal abundance, only one strand—designated as mature miR-21—is selectively incorporated into the RNA-induced silencing complex (RISC), based on the thermodynamic stability of the duplex ends. The other strand, labeled miR-21*, is typically degraded. The mature miRNA then guides the RISC complex to target mRNAs, usually binding near-perfectly to sequences within the 3'UTR.

Function

MicroRNA-21 is a highly conserved small noncoding RNA that plays a central role in regulating gene expression across a broad range of biological processes, including development, immune response, and cellular homeostasis. It modulates immune system activity by regulating T cell effector functions and maintaining the balance between Th1 and Th2 responses.

Targets

A number of targets for microRNA-21 have been experimentally validated and most of them are tumor suppressors, Notable targets include:

• ANP32A,
• BTG2,
• Bcl2,
• P12/CDK2AP1,
• HNRPK,
• IL-12p35,
• JAG1,
• MEF2C,
• hMSH2,
• PDCD4,
• PTEN,
• RECK,
• RhoB,
• SMARCA4,
• TGFBRII,
• SPRY1,
• SPRY2,
• TP63, and
• Tropomyosin.

Clinical significance

Cancer

miR-21 is frequently overexpressed in a wide variety of human cancers and is classified as a prototypical onco-miR. It promotes tumorigenesis, metastasis, and resistance to therapy by targeting a range of tumor suppressor genes and signaling pathways. Dysregulation of miR-21 is also implicated in various non-cancerous diseases, including cardiovascular and inflammatory conditions, underscoring its broad role in human pathology.

miR-21 is one of the most frequently upregulated miRNAs in solid tumours, and its high levels were first described in B cell lymphomas. Overall, miR-21 is considered to be a typical 'onco-miR', which acts by inhibiting the expression of phosphatases, which limit the activity of signalling pathways such as AKT and MAPK. As most of the targets of miR-21 are tumor suppressors, miR-21 is associated with a wide variety of cancers including that of lymphoma, breast, ovaries, cervix, colon, lung, liver, brain, esophagus, prostate, pancreas, and thyroid. In 2010, it was develop the first-in class in vivo model where a non-coding RNA (including a microRNA) is able to create and maintain a tumor in the first described onco-miRNA adicction. A 2014 meta-analysis of 36 studies evaluated circulating miR-21 as a biomarker of various carcinomas, finding it has potential as a tool for early diagnosis. miR-21 expression was associated with survival in 53 triple negative breast cancer patients. miR-21 can also be detected in human faeces from colorectal cancer patients. Additionally, it has been demonstrated as an independent prognostic factor in patients with pancreatic neuroendocrine neoplasms.

Cardiac disease

miR-21 has been shown to play important role in development of heart disease. It is one of the microRNAs whose expression is increased in failing murine and human hearts. Further, inhibition of microRNAs in mice using chemically modified and cholesterol-conjugated miRNA inhibitors (antagomirs) was shown to inhibit interstitial fibrosis and improve cardiac function in a pressure- overload cardiac disease mice model. Surprisingly, miR-21 global knock-out mice did not show any overt phenotype when compared with wild type mice with respect to cardiac stress response. Similarly, short (8-nt) oligonucleotides designed to inhibit miR-21 could not inhibit cardiac hypertrophy or fibrosis. In another study with a mouse model of acute myocardial infarction, miR-21 expression was found to be significantly lower in infarcted areas and overexpression of miR-21 in those mice via adenovirus-mediated gene transfer decreased myocardial infarct size. miR-21 has been hypothesized to be an intermediary in the effects of air pollution that lead to endothelial dysfunction and eventually to cardiac disease. Expression of miR-21 is negatively associated with exposure to PM10 air pollution and may mediate its effect on small blood vessels.

References

References

1. (October 2001). "Identification of novel genes coding for small expressed RNAs". Science.
2. (2011). "Regulation and function of miRNA-21 in health and disease". RNA Biology.
3. (September 2011). "MicroRNA-21 limits in vivo immune response-mediated activation of the IL-12/IFN-gamma pathway, Th1 polarization, and the severity of delayed-type hypersensitivity". Journal of Immunology.
4. (July 2009). "Regulation of the cell cycle gene, BTG2, by miR-21 in human laryngeal carcinoma". Cell Research.
5. (May 2009). "Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells". Nucleic Acids Research.
6. (March 2011). "miR-21 downregulates the tumor suppressor P12 CDK2AP1 and stimulates cell proliferation and invasion". Journal of Cellular Biochemistry.
7. (April 2009). "MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression". Journal of Immunology.
8. (July 2009). "MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation". Blood.
9. (September 2010). "MicroRNA-21 dysregulates the expression of MEF2C in neurons in monkey and human SIV/HIV neurological disease". Cell Death & Disease.
10. (December 2010). "MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2)". Proceedings of the National Academy of Sciences of the United States of America.
11. (April 2008). "MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer". Oncogene.
12. (August 2007). "MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer". Gastroenterology.
13. (September 2008). "MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators". Molecular and Cellular Biology.
14. (February 2011). "MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells". PLOS ONE.
15. (June 2011). "MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4". Oncogene.
16. (December 2009). "MiR-21 regulates adipogenic differentiation through the modulation of TGF-beta signaling in mesenchymal stem cells derived from human adipose tissue". Stem Cells.
17. (December 2008). "MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts". Nature.
18. (August 2008). "MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths". Molecular Biology of the Cell.
19. (October 2008). "MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells". Cancer Research.
20. (October 2016). "Emerging role of microRNA-21 in cancer". Biomedical Reports.
21. (2014). "MicroRNA-21 identified as predictor of cancer outcome: a meta-analysis". PLOS ONE.
22. (September 2022). "From Molecular Mechanisms to Therapeutics: Understanding MicroRNA-21 in Cancer". Cells.
23. (December 2021). "The Role of hsa-miR-21 and Its Target Genes Involved in Nasopharyngeal Carcinoma". Asian Pacific Journal of Cancer Prevention.
24. (September 2010). "OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma". Nature.
25. (August 2005). "MicroRNA gene expression deregulation in human breast cancer". Cancer Research.
26. (September 2007). "MicroRNA signatures in human ovarian cancer". Cancer Research.
27. (July 2007). "Patterns of known and novel small RNAs in human cervical cancer". Cancer Research.
28. (February 2006). "A microRNA expression signature of human solid tumors defines cancer gene targets". Proceedings of the National Academy of Sciences of the United States of America.
29. (July 2005). "MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells". Cancer Research.
30. (January 2011). "Prognostic significance of differentially expressed miRNAs in esophageal cancer". International Journal of Cancer.
31. (2007). "Differential expression of miRNAs in papillary thyroid carcinoma compared to multinodular goiter using formalin fixed paraffin embedded tissues". Endocrine Pathology.
32. (September 2010). "Cancer: miRNA addiction - depending on life's little things". Current Biology.
33. (March 2015). "Circulating microRNA-21 as a biomarker for the detection of various carcinomas: an updated meta-analysis based on 36 studies". Tumour Biology.
34. (December 2016). "miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients". Breast Cancer Research and Treatment.
35. (July 2019). "Faecal microRNAs as a non-invasive tool in the diagnosis of colonic adenomas and colorectal cancer: A meta-analysis". Scientific Reports.
36. (July 2018). "Prognostic relevance of proliferation-related miRNAs in pancreatic neuroendocrine neoplasms". European Journal of Endocrinology.
37. (April 2009). "MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue". Cardiovascular Research.
38. (November 2010). "Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice". The Journal of Clinical Investigation.
39. (October 2009). "MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction". The Journal of Biological Chemistry.
40. (May 2016). "miRNA expression profiles and retinal blood vessel calibers are associated with short-term particulate matter air pollution exposure". Environmental Research.