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miR-375
Conserved secondary structure of mir-375
Identifiers
Symbolmir-375
RfamRF00700
miRBase familyMIPF0000114
Other data
RNA typemicroRNA
Domain(s)Eukaryota;
PDB structuresPDBe

The miR-375 microRNA (miRNA) is a short RNA molecule located on human chromosome 2 in between the CRYBA2 and CCDC108 genes[1]. miRNAs are small (18–25 nucleotides), non-coding RNAs that regulate genes post-transcriptionally by inhibiting translation and/or causing mRNA degradation[1]. miR-375 is specifically expressed in the pancreatic islets, brain and spinal cord[2][3]. 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[4]. These processes are related to diabetes because pancreatic islets contain β-cells that produce insulin, a hormone that regulates blood sugar[5]. 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[5]. In patients with type 2 diabetes, β-cell mass is reduced by up to 60% when compared to healthy individuals[6]. Similarly, there is a decrease in β-cell mass per pancreatic area when miR-375 is knocked out in mice[7]. In addition, miR-375 shows elevated expression levels during pancreatic development, which coincide with higher insulin expression and β-cell proliferation[4][5]. Thus, evidence suggests that miR-375 is important for normal pancreatic islet formation and insulin secretion from β-cells[5]. Because of the role miR-375 plays in regulating processes essential for healthy sugar metabolism, it may be a potential target for treating diabetes[5].

Diabetes is currently managed with exogenous insulin and islet cell transplantation[5]. 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[5]. 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[5]. As such, hESCs have the potential to provide a limitless source of insulin-producing β-cells[5]. 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[5]. 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[5]. Therefore, miR-375 is a promising target for the treatment of diabetes.

Involvement 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[8].

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[9][10][11]. In vivo studies in mouse models of HCC also show reduced tumour growth with no apparent side effects[9][10][11]. 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[12]. The PI3K/Akt signalling pathway promotes aerobic glycolysis, which is a hallmark of rapidly dividing cancer cells[12]. 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 [13].

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)[4]. 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)[14]. In patients with T1DM, miR-375 dysregulation was observed in a number of tissues that were directly linked to the development of the disease[15]. 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[16]. 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)[17].

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[19].

References

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  1. ^ a b Baroukh, Nadine N.; Van Obberghen, Emmanuel (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.
  2. ^ Avnit-Sagi, Tali; Kantorovich, Lia; Kredo-Russo, Sharon; Hornstein, Eran; Walker, Michael D. (3 April 2009). "The Promoter of the pri-miR-375 Gene Directs Expression Selectively to the Endocrine Pancreas". PLoS ONE. 4 (4): e5033. doi:10.1371/journal.pone.0005033.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ Bhinge, Akshay; Namboori, Seema C.; Bithell, Angela; Soldati, Chiara; Buckley, Noel J.; Stanton, Lawrence W. (1 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.
  4. ^ a b c Liu, Yang; Wang, Qiuyuan; Wen, Jie; Wu, Yiru; Man, Chaolai (2021-06-15). "MiR-375: A novel multifunctional regulator". Life Sciences. 275: 119323. doi:10.1016/j.lfs.2021.119323. ISSN 0024-3205.
  5. ^ a b c d e f g h i j k Li, Xueling (2014-01-01). "miR-375, a microRNA related to diabetes". Gene. 533 (1): 1–4. doi:10.1016/j.gene.2013.09.105. ISSN 0378-1119.
  6. ^ Wysham, Carol; Shubrook, Jay (2020-11-16). "Beta-cell failure in type 2 diabetes: mechanisms, markers, and clinical implications". Postgraduate Medicine. 132 (8): 676–686. doi:10.1080/00325481.2020.1771047. ISSN 0032-5481. PMID 32543261.
  7. ^ Poy, Matthew N.; Hausser, Jean; Trajkovski, Mirko; Braun, Matthias; Collins, Stephan; Rorsman, Patrik; Zavolan, Mihaela; Stoffel, Markus (2009-04-07). "miR-375 maintains normal pancreatic α- and β-cell mass". Proceedings of the National Academy of Sciences. 106 (14): 5813–5818. doi:10.1073/pnas.0810550106. ISSN 0027-8424. PMC 2656556. PMID 19289822.{{cite journal}}: CS1 maint: PMC format (link)
  8. ^ He, X.-X.; Chang, Y.; Meng, F.-Y.; Wang, M.-Y.; Xie, Q.-H.; Tang, F.; Li, P.-Y.; Song, Y.-H.; Lin, J.-S. (2012-07). "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. ISSN 1476-5594. {{cite journal}}: Check date values in: |date= (help)
  9. ^ a b Xue, Hui-Ying; Liu, Yong; Liao, Jia-Zhi; Lin, Ju-Sheng; Li, Bin; Yuan, Wei-Gang; Lee, Robert J.; Li, Lei; Xu, Chuan-Rui; He, Xing-Xing (2016-12-27). "Gold nanoparticles delivered miR-375 for treatment of hepatocellular carcinoma". Oncotarget. 7 (52): 86675–86686. doi:10.18632/oncotarget.13431. ISSN 1949-2553. PMC 5349944. PMID 27880727.{{cite journal}}: CS1 maint: PMC format (link)
  10. ^ a b Fan, Yin-Ping; Liao, Jia-Zhi; Lu, Ya-Qi; Tian, De-An; Ye, Feng; Zhao, Peng-Xuan; Xiang, Guang-Ya; Tang, Wang-Xian; He, Xing-Xing (2017-06). "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. {{cite journal}}: Check date values in: |date= (help)
  11. ^ a b Zhao, Pengxuan; Li, Minsi; Wang, Yao; Chen, Yan; He, Chuanchuan; Zhang, Xiaojuan; Yang, Tan; Lu, Yao; You, Jia; Lee, Robert J.; Xiang, Guangya (2018-05-01). "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. ISSN 1742-7061.
  12. ^ a b Kong, Kar Lok; Kwong, Dora Lai Wan; Chan, Tim Hon-Man; Law, Simon Ying-Kit; Chen, Leilei; Li, Yan; Qin, Yan-Ru; Guan, Xin-Yuan (1 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:https://doi.org/10.1136/gutjnl-2011-300178. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  13. ^ Renwick, Neil; Cekan, Pavol; Masry, Paul A.; McGeary, Sean E.; Miller, Jason B.; Hafner, Markus; Li, Zhen; Mihailovic, Aleksandra; Morozov, Pavel; Brown, Miguel; Gogakos, Tasos; Mobin, Mehrpouya B.; Snorrason, Einar L.; Feilotter, Harriet E.; Zhang, Xiao; Perlis, Clifford S.; Wu, Hong; Suárez-Fariñas, Mayte; Feng, Huichen; Shuda, Masahiro; Moore, Patrick S.; Tron, Victor A.; Chang, Yuan; Tuschl, Thomas (3 June 2013). "Multicolor microRNA FISH effectively differentiates tumor types". Journal of Clinical Investigation. 123 (6): 2694–2702. doi:10.1172/JCI68760.
  14. ^ Schaefer, Jeremy S; Attumi, Taraq; Opekun, Antone R; Abraham, Bincy; Hou, Jason; Shelby, Harold; Graham, David Y; Streckfus, Charles; Klein, John R (2015-12). "MicroRNA signatures differentiate Crohn's disease from ulcerative colitis". BMC Immunology. 16 (1): 5. doi:10.1186/s12865-015-0069-0. ISSN 1471-2172. PMC 4335694. PMID 25886994. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  15. ^ Assmann, Taís S; Recamonde-Mendoza, Mariana; De Souza, Bianca M; Crispim, Daisy (2017-11). "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. ISSN 2049-3614. {{cite journal}}: Check date values in: |date= (help)
  16. ^ Qiu, Yanyan; Xu, Jinyi; Yang, Lihong; Zhao, Guihua; Ding, Jing; Chen, Qiong; Zhang, Na; Yang, Ruike; Wang, Jijing; Li, Shuaibing; Zhang, Luming (2021-03). "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. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Redka, Dar’ya S.; Gütschow, Michael; Grinstein, Sergio; Canton, Johnathan (2018-01-01). "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. ISSN 1059-1524. PMC 5746066. PMID 29093026.{{cite journal}}: CS1 maint: PMC format (link)
  18. ^ Qiu, Yanyan; Xu, Jinyi; Yang, Lihong; Zhao, Guihua; Ding, Jing; Chen, Qiong; Zhang, Na; Yang, Ruike; Wang, Jijing; Li, Shuaibing; Zhang, Luming (2021-03). "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. {{cite journal}}: Check date values in: |date= (help)
  19. ^ Frank, Ann-Christin; Ebersberger, Stefanie; Fink, Annika F.; Lampe, Sebastian; Weigert, Andreas; Schmid, Tobias; Ebersberger, Ingo; Syed, Shahzad Nawaz; Brüne, Bernhard (2019-03-08). "Apoptotic tumor cell-derived microRNA-375 uses CD36 to alter the tumor-associated macrophage phenotype". Nature Communications. 10 (1): 1135. doi:10.1038/s41467-019-08989-2. ISSN 2041-1723. PMC 6408494. PMID 30850595.
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