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Mir-375

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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; OMA:MIR375 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

494324

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Ensembl

ENSG00000198973

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UniProt

n
a

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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 search[2]n/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.[3] miRNAs are small (18–25 nucleotides), non-coding RNAs that regulate genes post-transcriptionally by inhibiting translation and/or causing mRNA degradation.[3] miR-375 is specifically expressed in the pancreatic islets, brain and spinal cord.[4][5] Genetic manipulation of miR-375 levels can decrease cancer development and autoimmunity in affected cell types.

Roles in development

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Diabetes

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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.[6] These processes are related to diabetes because pancreatic islets contain β-cells that produce insulin, a hormone that regulates blood sugar.[7] 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.[7] In patients with type 2 diabetes, β-cell mass is reduced by up to 60% when compared to healthy individuals.[8] Similarly, there is a decrease in β-cell mass per pancreatic area when miR-375 is knocked out in mice.[9] In addition, miR-375 shows elevated expression levels during pancreatic development, which coincide with higher insulin expression and β-cell proliferation.[6][7] Thus, evidence suggests that miR-375 is important for normal pancreatic islet formation and insulin secretion from β-cells.[7] Because of the role miR-375 plays in regulating processes essential for healthy sugar metabolism, it may be a potential target for treating diabetes.[7]

Diabetes is currently managed with exogenous insulin and islet cell transplantation.[7] 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.[7] 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.[7] As such, hESCs have the potential to provide a limitless source of insulin-producing β-cells.[7] 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.[7] 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.[7] Therefore, miR-375 is a promising target for the treatment of diabetes.

Roles in cancer

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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.[10]

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.[11][12][13] In vivo studies in mouse models of HCC also show reduced tumour growth with no apparent side effects.[11][12][13] 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.[14] The PI3K/Akt signalling pathway promotes aerobic glycolysis, which is a hallmark of rapidly dividing cancer cells.[14] 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.[15]

Immunity

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miR-375 is involved in many autoimmune diseases, such as inflammatory bowel diseases (IBD) and type 1 diabetes mellitus (T1DM).[6] 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).[16] In patients with T1DM, miR-375 dysregulation was observed in a number of tissues that were directly linked to the development of the disease.[17] 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.[18] 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).[19]

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.[18] Interestingly, miR-375 enhances macrophage migration into cancer cells by targeting PNX and TSN3, which are both proteins involved maintaining cell structure and organization.[20]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198973 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ a b 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. ^ a b c 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. ^ a b c d e f g h i j k 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. ^ a b 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. ^ a b 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. ^ a b 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. ^ a b 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. ^ a b 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

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