Biology:mIRN21

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Short description: Non-coding RNA in the species Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

microRNA 21 also known as hsa-mir-21 or miRNA21 is a mammalian microRNA that is encoded by the MIR21 gene.[1]

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.[2] It modulates immune system activity by regulating T cell effector functions and maintaining the balance between Th1 and Th2 responses.[3]

Targets

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

Clinical significance

Cancer

miR-21 is frequently overexpressed in a wide variety of human cancers and is classified as a prototypical onco-miR.[20][21][22] It promotes tumorigenesis, metastasis, and resistance to therapy by targeting a range of tumor suppressor genes and signaling pathways.[20][23] Dysregulation of miR-21 is also implicated in various non-cancerous diseases, including cardiovascular and inflammatory conditions, underscoring its broad role in human pathology.[2][20]

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,[24] breast,[25] ovaries,[26] cervix,[27] colon,[12] lung,[28] liver,[13] brain,[29] esophagus,[30] prostate,[28] pancreas,[28] and thyroid.[31] 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[24] in the first described onco-miRNA adicction.[32] 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.[33] miR-21 expression was associated with survival in 53 triple negative breast cancer patients.[34] miR-21 can also be detected in human faeces from colorectal cancer patients.[35] Additionally, it has been demonstrated as an independent prognostic factor in patients with pancreatic neuroendocrine neoplasms.[36]

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.[18][37] 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.[18] 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.[38] 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.[39] 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.[40]

References

  1. ↑ "Identification of novel genes coding for small expressed RNAs". Science (New York, N.Y.) 294 (5543): 853–858. October 2001. doi:10.1126/science.1064921. PMID 11679670. Bibcode: 2001Sci...294..853L. 
  2. ↑ 2.0 2.1 "Regulation and function of miRNA-21 in health and disease". RNA Biology 8 (5): 706–713. 2011. doi:10.4161/rna.8.5.16154. PMID 21712654. 
  3. ↑ "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 (Baltimore, Md.) 187 (6): 3362–3373. September 2011. doi:10.4049/jimmunol.1101235. PMID 21849676. 
  4. ↑ "Regulation of the cell cycle gene, BTG2, by miR-21 in human laryngeal carcinoma". Cell Research 19 (7): 828–837. July 2009. doi:10.1038/cr.2009.72. PMID 19546886. 
  5. ↑ "Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells". Nucleic Acids Research 37 (8): 2584–2595. May 2009. doi:10.1093/nar/gkp117. PMID 19264808. 
  6. ↑ "miR-21 downregulates the tumor suppressor P12 CDK2AP1 and stimulates cell proliferation and invasion". Journal of Cellular Biochemistry 112 (3): 872–880. March 2011. doi:10.1002/jcb.22995. PMID 21328460. 
  7. ↑ 7.0 7.1 7.2 "MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells". Cancer Research 68 (19): 8164–8172. October 2008. doi:10.1158/0008-5472.CAN-08-1305. PMID 18829576. 
  8. ↑ "MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression". Journal of Immunology (Baltimore, Md.) 182 (8): 4994–5002. April 2009. doi:10.4049/jimmunol.0803560. PMID 19342679. 
  9. ↑ "MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation". Blood 114 (2): 404–414. July 2009. doi:10.1182/blood-2008-09-179150. PMID 19398721. 
  10. ↑ "MicroRNA-21 dysregulates the expression of MEF2C in neurons in monkey and human SIV/HIV neurological disease". Cell Death & Disease 1 (9): e77. September 2010. doi:10.1038/cddis.2010.56. PMID 21170291. 
  11. ↑ "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 107 (49): 21098–21103. December 2010. doi:10.1073/pnas.1015541107. PMID 21078976. Bibcode: 2010PNAS..10721098V. 
  12. ↑ 12.0 12.1 "MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer". Oncogene 27 (15): 2128–2136. April 2008. doi:10.1038/sj.onc.1210856. PMID 17968323. 
  13. ↑ 13.0 13.1 "MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer". Gastroenterology 133 (2): 647–658. August 2007. doi:10.1053/j.gastro.2007.05.022. PMID 17681183. 
  14. ↑ "MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators". Molecular and Cellular Biology 28 (17): 5369–5380. September 2008. doi:10.1128/MCB.00479-08. PMID 18591254. 
  15. ↑ "MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells". PLOS ONE 6 (2). February 2011. doi:10.1371/journal.pone.0016979. PMID 21347332. Bibcode: 2011PLoSO...616979S. 
  16. ↑ "MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4". Oncogene 30 (26): 2975–2985. June 2011. doi:10.1038/onc.2011.15. PMID 21317927. 
  17. ↑ "MiR-21 regulates adipogenic differentiation through the modulation of TGF-beta signaling in mesenchymal stem cells derived from human adipose tissue". Stem Cells (Dayton, Ohio) 27 (12): 3093–3102. December 2009. doi:10.1002/stem.235. PMID 19816956. 
  18. ↑ 18.0 18.1 18.2 "MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts". Nature 456 (7224): 980–984. December 2008. doi:10.1038/nature07511. PMID 19043405. Bibcode: 2008Natur.456..980T. 
  19. ↑ "MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths". Molecular Biology of the Cell 19 (8): 3272–3282. August 2008. doi:10.1091/mbc.E08-02-0159. PMID 18508928. 
  20. ↑ 20.0 20.1 20.2 "Emerging role of microRNA-21 in cancer". Biomedical Reports 5 (4): 395–402. October 2016. doi:10.3892/br.2016.747. PMID 27699004. 
  21. ↑ "MicroRNA-21 identified as predictor of cancer outcome: a meta-analysis". PLOS ONE 9 (8). 2014. doi:10.1371/journal.pone.0103373. PMID 25098165. Bibcode: 2014PLoSO...9j3373Z. 
  22. ↑ "From Molecular Mechanisms to Therapeutics: Understanding MicroRNA-21 in Cancer". Cells 11 (18): 2791. September 2022. doi:10.3390/cells11182791. PMID 36139366. 
  23. ↑ "The Role of hsa-miR-21 and Its Target Genes Involved in Nasopharyngeal Carcinoma". Asian Pacific Journal of Cancer Prevention 22 (12): 4075–4083. December 2021. doi:10.31557/APJCP.2021.22.12.4075. PMID 34967592. 
  24. ↑ 24.0 24.1 "OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma". Nature 467 (7311): 86–90. September 2010. doi:10.1038/nature09284. PMID 20693987. Bibcode: 2010Natur.467...86M. 
  25. ↑ "MicroRNA gene expression deregulation in human breast cancer". Cancer Research 65 (16): 7065–7070. August 2005. doi:10.1158/0008-5472.CAN-05-1783. PMID 16103053. 
  26. ↑ "MicroRNA signatures in human ovarian cancer". Cancer Research 67 (18): 8699–8707. September 2007. doi:10.1158/0008-5472.CAN-07-1936. PMID 17875710. 
  27. ↑ "Patterns of known and novel small RNAs in human cervical cancer". Cancer Research 67 (13): 6031–6043. July 2007. doi:10.1158/0008-5472.CAN-06-0561. PMID 17616659. 
  28. ↑ 28.0 28.1 28.2 "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 103 (7): 2257–2261. February 2006. doi:10.1073/pnas.0510565103. PMID 16461460. Bibcode: 2006PNAS..103.2257V. 
  29. ↑ "MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells". Cancer Research 65 (14): 6029–6033. July 2005. doi:10.1158/0008-5472.CAN-05-0137. PMID 16024602. 
  30. ↑ "Prognostic significance of differentially expressed miRNAs in esophageal cancer". International Journal of Cancer 128 (1): 132–143. January 2011. doi:10.1002/ijc.25330. PMID 20309880. 
  31. ↑ "Differential expression of miRNAs in papillary thyroid carcinoma compared to multinodular goiter using formalin fixed paraffin embedded tissues". Endocrine Pathology 18 (3): 163–173. 2007. doi:10.1007/s12022-007-0023-7. PMID 18058265. 
  32. ↑ "Cancer: miRNA addiction - depending on life's little things". Current Biology 20 (18): R812–R813. September 2010. doi:10.1016/j.cub.2010.08.040. PMID 20869610. Bibcode: 2010CBio...20.R812D. 
  33. ↑ "Circulating microRNA-21 as a biomarker for the detection of various carcinomas: an updated meta-analysis based on 36 studies". Tumour Biology 36 (3): 1973–1981. March 2015. doi:10.1007/s13277-014-2803-2. PMID 25527152. 
  34. ↑ "miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients". Breast Cancer Research and Treatment 160 (3): 439–446. December 2016. doi:10.1007/s10549-016-4013-7. PMID 27744485. 
  35. ↑ "Faecal microRNAs as a non-invasive tool in the diagnosis of colonic adenomas and colorectal cancer: A meta-analysis". Scientific Reports 9 (1). July 2019. doi:10.1038/s41598-019-45570-9. PMID 31263200. Bibcode: 2019NatSR...9.9491Y. 
  36. ↑ "Prognostic relevance of proliferation-related miRNAs in pancreatic neuroendocrine neoplasms". European Journal of Endocrinology 179 (4): EJE–18–0305. July 2018. doi:10.1530/EJE-18-0305. PMID 30006373. http://www.eje-online.org/content/early/2018/07/13/EJE-18-0305. 
  37. ↑ "MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue". Cardiovascular Research 82 (1): 21–9. April 2009. doi:10.1093/cvr/cvp015. PMID 19147652. 
  38. ↑ "Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice". The Journal of Clinical Investigation 120 (11): 3912–6. November 2010. doi:10.1172/JCI43604. PMID 20978354. 
  39. ↑ "MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction". The Journal of Biological Chemistry 284 (43): 29514–25. October 2009. doi:10.1074/jbc.M109.027896. PMID 19706597. 
  40. ↑ "miRNA expression profiles and retinal blood vessel calibers are associated with short-term particulate matter air pollution exposure". Environmental Research 147: 24–31. May 2016. doi:10.1016/j.envres.2016.01.027. PMID 26836502. Bibcode: 2016ER....147...24L. 

Further reading



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