Mir-375

mir-375
Conserved secondary structure of mir-375
Identifiers
Symbolmir-375
RfamRF00700
miRBase familyMIPF0000114
Other data
RNA typemicroRNA
DomainEukaryota;
PDB structuresPDBe
Mir-375
Identifiers
AliasesMIR375, MIRN375, hsa-mir-375, miRNA375, mir-375, microRNA 375
External IDsOMIM: 611173; GeneCards: MIR375
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

494324

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Ensembl

ENSG00000198973

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)Chr 2: 219 – 219 Mbn/a
PubMed searchn/a
Wikidata
View/Edit Human

The miR-375 microRNA (miRNA) is a short RNA molecule located on human chromosome 2 in between the CRYBA2 and CCDC108 genes. miRNAs are small (18–25 nucleotides), non-coding RNAs that regulate genes post-transcriptionally by inhibiting translation and/or causing mRNA degradation. miR-375 is specifically expressed in the pancreatic islets, brain and spinal cord. Genetic manipulation of miR-375 levels can decrease cancer development and autoimmunity in affected cell types.

Roles in development

Diabetes

miR-375 plays a critical role in diabetes by regulating the expression of related genes involved in pancreatic islet formation, pancreatic development, and β-cell secretion. These processes are related to diabetes because pancreatic islets contain β-cells that produce insulin, a hormone that regulates blood sugar. A person with diabetes will have high blood sugar either because their cells are not responding to insulin or because their pancreatic beta cells are not producing enough of it. In patients with type 2 diabetes, β-cell mass is reduced by up to 60% when compared to healthy individuals. Similarly, there is a decrease in β-cell mass per pancreatic area when miR-375 is knocked out in mice. In addition, miR-375 shows elevated expression levels during pancreatic development, which coincide with higher insulin expression and β-cell proliferation. Thus, evidence suggests that miR-375 is important for normal pancreatic islet formation and insulin secretion from β-cells. Because of the role miR-375 plays in regulating processes essential for healthy sugar metabolism, it may be a potential target for treating diabetes.

Diabetes is currently managed with exogenous insulin and islet cell transplantation. However, these treatments fall short in their attempts to reestablish the natural regulation of blood sugar and are limited by the scarcity of donor tissue, respectively. To address these concerns, scientists have begun investigating the potential of human embryonic stem cells (hESCs), which are cells that can develop into many adult cell types including pancreatic β-cells. As such, hESCs have the potential to provide a limitless source of insulin-producing β-cells. However, creating mature β-cells from hESCs has proved challenging for researchers because the hESC-derived cells often secreted other hormones in addition to insulin. miR-375 may provide a new way to mature hESCs into β-cells because of its high expressivity in β-cells and its function in insulin release. Therefore, miR-375 is a promising target for the treatment of diabetes.

Roles in cancer

Affected organ Proposed mechanisms/applications
Liver In cancerous liver cells, known as hepatocellular carcinomas (HCC), miR-375 acts as a tumour suppressor. This was evidenced by a decrease in the rate of uncontrolled cell division through the inhibition of a well-known oncogene, AEG-1, in response to miR-375 overexpression.

Recent studies show that when miR-375 is introduced into HCC cell lines, there is a reduction in cell proliferation, motility, and migration, as well as an increase in apoptosis in vitro. In vivo studies in mouse models of HCC also show reduced tumour growth with no apparent side effects. These results support potential strategies to increase miR-375 levels in HCCs to prevent metastasis.

Esophagus miR-375 overexpression inhibits tumour growth and metastasis of esophageal cancer cells by inhibiting insulin-like growth factor 1 receptor and proteins involved in the PI3K/Akt signalling pathway. The PI3K/Akt signalling pathway promotes aerobic glycolysis, which is a hallmark of rapidly dividing cancer cells. Hence, a potential strategy for inhibiting proliferation in esophageal cancer cells would be to increase intracellular miR-375 levels.
Skin Increased expression of miR-375 in Merkel cell carcinomas (MCC) is used as a marker to differentiate MCC from other common skin cancers.

Immunity

miR-375 is involved in many autoimmune diseases, such as inflammatory bowel diseases (IBD) and type 1 diabetes mellitus (T1DM). For instance, miR-375 can be used as a factor to distinguish between the different types of IBD (e.g. Crohn's disease vs ulcerative colitis). In patients with T1DM, miR-375 dysregulation was observed in a number of tissues that were directly linked to the development of the disease. Furthermore, miR-375 is involved in the molecular aspects of immunity as miR-375 silencing decreases the production of pro-inflammatory macrophages and subsequent inflammatory response. While pro-inflammatory macrophages are responsible for killing pathogens, a sustained pro-inflammatory response leads to a long list of disorders (e.g. arthritis, asthma, atherosclerosis, blindness, cancer, and diabetes).

Since miR-375 silencing inhibits the production of pro-inflammatory macrophages, it can delay the onset of atherosclerosis (the main underlying cause of heart attacks and strokes) in mice, indicating its therapeutic potential in conditions accompanied by chronic inflammation. Interestingly, miR-375 enhances macrophage migration into cancer cells by targeting PNX and TSN3, which are both proteins involved maintaining cell structure and organization.

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000198973 – Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 Baroukh NN, Van Obberghen E (November 2009). "Function of microRNA-375 and microRNA-124a in pancreas and brain: Function of miR-375 and 124a in pancreas and brain". FEBS Journal. 276 (22): 6509–6521. doi:10.1111/j.1742-4658.2009.07353.x. PMID 20102393. S2CID 45784402.
  4. ↑ Avnit-Sagi T, Kantorovich L, Kredo-Russo S, Hornstein E, Walker MD (2009). "The promoter of the pri-miR-375 gene directs expression selectively to the endocrine pancreas". PLOS ONE. 4 (4) e5033. Bibcode:2009PLoSO...4.5033A. doi:10.1371/journal.pone.0005033. PMC 2660411. PMID 19343226.
  5. ↑ Bhinge A, Namboori SC, Bithell A, Soldati C, Buckley NJ, Stanton LW (January 2016). "MiR-375 is Essential for Human Spinal Motor Neuron Development and May Be Involved in Motor Neuron Degeneration". Stem Cells. 34 (1): 124–134. doi:10.1002/stem.2233. PMID 26507573. S2CID 26250020.
  6. 1 2 3 Liu Y, Wang Q, Wen J, Wu Y, Man C (June 2021). "MiR-375: A novel multifunctional regulator". Life Sciences. 275 119323. doi:10.1016/j.lfs.2021.119323. PMID 33744323. S2CID 232309025.
  7. 1 2 3 4 5 6 7 8 9 10 11 Li X (January 2014). "MiR-375, a microRNA related to diabetes". Gene. 533 (1): 1–4. doi:10.1016/j.gene.2013.09.105. PMID 24120394.
  8. ↑ Wysham C, Shubrook J (November 2020). "Beta-cell failure in type 2 diabetes: mechanisms, markers, and clinical implications". Postgraduate Medicine. 132 (8): 676–686. doi:10.1080/00325481.2020.1771047. PMID 32543261. S2CID 219705786.
  9. ↑ Poy MN, Hausser J, Trajkovski M, Braun M, Collins S, Rorsman P, et al. (April 2009). "miR-375 maintains normal pancreatic alpha- and beta-cell mass". Proceedings of the National Academy of Sciences of the United States of America. 106 (14): 5813–5818. Bibcode:2009PNAS..106.5813P. doi:10.1073/pnas.0810550106. PMC 2656556. PMID 19289822.
  10. ↑ He XX, Chang Y, Meng FY, Wang MY, Xie QH, Tang F, et al. (July 2012). "MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo". Oncogene. 31 (28): 3357–3369. doi:10.1038/onc.2011.500. PMID 22056881. S2CID 2050305.
  11. 1 2 Xue HY, Liu Y, Liao JZ, Lin JS, Li B, Yuan WG, et al. (December 2016). "Gold nanoparticles delivered miR-375 for treatment of hepatocellular carcinoma". Oncotarget. 7 (52): 86675–86686. doi:10.18632/oncotarget.13431. PMC 5349944. PMID 27880727.
  12. 1 2 Fan YP, Liao JZ, Lu YQ, Tian DA, Ye F, Zhao PX, et al. (June 2017). "MiR-375 and Doxorubicin Co-delivered by Liposomes for Combination Therapy of Hepatocellular Carcinoma". Molecular Therapy. Nucleic Acids. 7: 181–189. doi:10.1016/j.omtn.2017.03.010. PMC 5415965. PMID 28624193. S2CID 42833717.
  13. 1 2 Zhao P, Li M, Wang Y, Chen Y, He C, Zhang X, et al. (May 2018). "Enhancing anti-tumor efficiency in hepatocellular carcinoma through the autophagy inhibition by miR-375/sorafenib in lipid-coated calcium carbonate nanoparticles". Acta Biomaterialia. 72: 248–255. doi:10.1016/j.actbio.2018.03.022. PMID 29555460.
  14. 1 2 Kong KL, Kwong DL, Chan TH, Law SY, Chen L, Li Y, et al. (January 2012). "MicroRNA-375 inhibits tumour growth and metastasis in oesophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor". Gut. 61 (1): 33–42. doi:10.1136/gutjnl-2011-300178. hdl:10722/144525. PMID 21813472. S2CID 36516750.
  15. ↑ Renwick N, Cekan P, Masry PA, McGeary SE, Miller JB, Hafner M, et al. (June 2013). "Multicolor microRNA FISH effectively differentiates tumor types". The Journal of Clinical Investigation. 123 (6): 2694–2702. doi:10.1172/JCI68760. PMC 3668843. PMID 23728175.
  16. ↑ Schaefer JS, Attumi T, Opekun AR, Abraham B, Hou J, Shelby H, et al. (February 2015). "MicroRNA signatures differentiate Crohn's disease from ulcerative colitis". BMC Immunology. 16 (1) 5. doi:10.1186/s12865-015-0069-0. PMC 4335694. PMID 25886994.
  17. ↑ Assmann TS, Recamonde-Mendoza M, De Souza BM, Crispim D (November 2017). "MicroRNA expression profiles and type 1 diabetes mellitus: systematic review and bioinformatic analysis". Endocrine Connections. 6 (8): 773–790. doi:10.1530/ec-17-0248. PMC 5682418. PMID 28986402.
  18. 1 2 Qiu Y, Xu J, Yang L, Zhao G, Ding J, Chen Q, et al. (March 2021). "MiR-375 silencing attenuates pro-inflammatory macrophage response and foam cell formation by targeting KLF4". Experimental Cell Research. 400 (1) 112507. doi:10.1016/j.yexcr.2021.112507. PMID 33545131. S2CID 231963270.
  19. ↑ Redka DS, Gütschow M, Grinstein S, Canton J (January 2018). "Differential ability of proinflammatory and anti-inflammatory macrophages to perform macropinocytosis". Molecular Biology of the Cell. 29 (1): 53–65. doi:10.1091/mbc.E17-06-0419. PMC 5746066. PMID 29093026.
  20. ↑ Frank AC, Ebersberger S, Fink AF, Lampe S, Weigert A, Schmid T, et al. (March 2019). "Apoptotic tumor cell-derived microRNA-375 uses CD36 to alter the tumor-associated macrophage phenotype". Nature Communications. 10 (1) 1135. Bibcode:2019NatCo..10.1135F. doi:10.1038/s41467-019-08989-2. PMC 6408494. PMID 30850595.

Further reading