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MiR-125

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MicroRNA-125 (miR-125) is a highly conserved microRNA family consisting of miR-125a and miR-125b.[1] [2]MiR-125 can be found throughout diverse species from nematode to humans. MiR-125 family members are involved in cell differentiation, proliferation and apoptosis as a result of targeting messenger RNAs related to these cellular processes.[3][4] By affecting these cellular processes, miR-125 can cause promotion or suppression of pathological processes including carcinogenesis, muscle abnormalities, neurological disorders and pathologies of the immune system. Moreover, miR-125 also plays an important role in normal immune functions and was described to affect development and function of immune cells as well as playing role in immunological host defense in response to bacterial and viral infections.[5]

Genome location and biogenesis

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Each member of miR-125 family has two different variants of mature miRNAs - 5p and 3p. Both variants originate from the same pre-miRNA. MiR-125-5p variant generally shows higher expression compared to miR-125-3p.[6] In humans, miR-125 family is composed of three homologs: hsa-miR-125a, hsa-miR-125b-1 and hsa-miR-125b-2.[7] MiR-125a has been found to be located on chromosome 19, while paralogs of miR-125b are transcribed from two loci on chromosome 11 and chromosome 21.[8]

Brain

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As a brain-enriched microRNA, miR-125b participates in neuronal differentiation but also in many diseases associated with degenerating brain tissues.

MiR-125b promotes neuronal differentiation, thus levels of this microRNA get higher during neurogenesis. MiR-125b can contribute to the process of neuronal differentiation by targeting cyclin-dependent kinase inhibitor 2A (CDKN2A), a negative regulator of the cell cycle. On the other hand, downregulation of CDKN2A correlates with chronic neurological disorders associated with astrogliosis, such as advanced Alzheimer disease.[9][10]

Muscle

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MiR-125 family is related to cardiomyocytes and the development of heart in embryonic period of mammals. Decreased levels of miR-125 can cause abnormal development of the cardiovascular system in these early stages.

MiR-125 plays role in a variety of cardiovascular and cerebrovascular diseases, in their occurrence and development. The same family members of miR-125 can play different roles in different pathological processes. For instance, high levels of miR-125b can protect cardiomyocytes from apoptosis and inflammation. While at the same time, overexpression of miR-125 can support cardiac fibrosis by enhancing proliferation of fibroblasts and reducing their apoptosis. Significantly increased levels of miR-125b have also been found in patients with heart failure.[11]

MiR-125b can also negatively regulate skeletal myoblast differentiation and muscle regeneration by targeting insulin-like growth factor II (IGF-II). Decreased levels of this microRNA were noted during these processes. However, overexpression of miR-125b, especially the miR-125b-5p form, can protect skeletal muscle from atrophy.[12][11]

Role in immune system

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Targets of miR-125 are involved in regulation of hematopoiesis, inflammation and many immune cells function. Different expression levels of miR-125 are found among different types of immune cells and stages of hematopoiesis.

Principally, expression of both miR-15a and miR-125b decreases during the process of cell differentiation.[13][14] Higher expression levels are found in hematopoietic stem cells (HSCs) and are associated with elevation of self-renewal and survival in these cells. Increased expression of miR-125a improves long-term multi-lineage repopulation and self-renewal of HSCs by blocking apoptosis pathways.[14] MiR-125b can even block terminal differentiation of hematopoietic progenitors and also regulate HSC homeostasis by shifting the balance of TGFβ and Wnt signaling pathways.[15][16] Additionally, miR-125b is associated with an impairment of B cell development and plays role in mainly negative regulation of T cell development.[6][17][5]

MiR-125b can affect inflammation by targeting TNF-α, enhancing the stability of NF-κB inhibitor NKIRAS2 and also by promotion of differentiation and activation of macrophages.[15][18] Increased levels of miR-125b may enhance expression of type I interferons and participate in antiviral defense. For instance, this miRNA contributes to HIV-1 latency by destabilization of HIV-1 transcript by binding to its 3' end. And miR-125a was described to interfere with transcript of hepatitis B virus.[19] MiR-125 can also participate in regulation of immune response against bacterial infection. Upregulated levels of miR-125 can contribute to turning off the TLR signaling in the absence of microbial infection. While downregulation of this miRNA can support inflammatory response.[20] MiR-125 was also described to suppress the development of rheumatoid arthritis by inhibition of PI3K/Akt/mTOR signalling pathway via PARP2 targeting.[21]

Role in carcinogenesis

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By targeting transcripts of genes such as transcription factors, matrix-metalloproteinases, Bcl-2 family gene members, small GTPases, miR-125 dysregulation may lead to abnormal metabolism, proliferation, cell invasion and metastasis. Effects of miR-125 in cancer are cell type dependent. MiR-125 is defined either as an oncogene or as a tumor suppressor and can promote or prevent tumor growth at various stages. The tumor promoter or suppressor role of miR-125 depends on cellular context and the same target may have different functions in different cellular processes and diseases. MiR-125 cancer research is often related to hematological malignancies.[19][5][15]

Upregulation of miR-125b occurs in patients with B-cell acute lymphoblastic leukemia, megakaryoblastic leukemia, myelodysplasia and acute myeloid leukemia.[19] While miR-125a acts as an oncogenic miRNA in non-blood cancers, its oncogenic functions have been described in cervical cancer, colorectal cancer, nasopharyngeal carcinoma and esophageal carcinomas.[5] On the other hand, high expression of miR-125b was shown to decrease cell proliferation and induces apoptosis. The cell ability of tumor formation may be reduced with increased levels of miR-125-b because of the PI3K/Akt/mTOR pathway targeting as was described in cervical cancer.[22] By targeting Bcl-2 family members transcripts, miR-125 is involved in regulation of apoptosis as well. Depending on the context and expression levels, this miRNA can either protect cells from apoptosis or promote this process.[5][19]

As a tumor suppressor miRNA, MiR-125 was described to occur in ovarian cancer, bladder cancer, breast cancer, hepatocellular carcinoma, melanoma, cutaneous squamous cell carcinoma, osteosarcoma, colorectal carcinoma, glioblastoma, renal cell carcinoma, thyroid cancer and prostate cancer.[5][19] In terms of tumor suppressive functions and mechanisms, miR-125 family has been described to directly or indirectly silence several oncogenic pathways, such as KRAS.[23] MiR-125 inhibits cell invasion and metastasis by targeting MMP11 and MMP13 matrix-metalloproteinases and small GTPases such as RhoA and Rac1[19] MiR-125 was also described to regulate angiogenesis via VEGF-A targeting.[24]

References

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  1. ^ Mehta, Arnav; Baltimore, David (May 2016). "MicroRNAs as regulatory elements in immune system logic". Nature Reviews Immunology. 16 (5): 279–294. doi:10.1038/nri.2016.40. ISSN 1474-1733. PMID 27121651. S2CID 7229814.
  2. ^ Qureshi A, Thakur N, Monga I, Thakur A, Kumar M (1 January 2014). "VIRmiRNA: a comprehensive resource for experimentally validated viral miRNAs and their targets". Database. 2014: bau103. doi:10.1093/database/bau103. PMC 4224276. PMID 25380780.
  3. ^ Bousquet, M.; Nguyen, D.; Chen, C.; Shields, L.; Lodish, H. F. (2012-06-11). "MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA". Haematologica. 97 (11): 1713–1721. doi:10.3324/haematol.2011.061515. ISSN 0390-6078. PMC 3487446. PMID 22689670.
  4. ^ Bi, Qian; Tang, Shanhong; Xia, Lin; Du, Rui; Fan, Rui; Gao, Liucun; Jin, Jiang; Liang, Shuhui; Chen, Zheng; Xu, Guanghui; Nie, Yongzhan (2012-06-29). "Ectopic Expression of MiR-125a Inhibits the Proliferation and Metastasis of Hepatocellular Carcinoma by Targeting MMP11 and VEGF". PLOS ONE. 7 (6): e40169. Bibcode:2012PLoSO...740169B. doi:10.1371/journal.pone.0040169. ISSN 1932-6203. PMC 3387011. PMID 22768249.
  5. ^ a b c d e f Wang, Jessica K.; Wang, Zhe; Li, Guideng (July 2019). "MicroRNA-125 in immunity and cancer". Cancer Letters. 454: 134–145. doi:10.1016/j.canlet.2019.04.015. PMID 30981762. S2CID 115203168.
  6. ^ a b Li, Guideng; So, Alex Yick-Lun; Sookram, Reeshelle; Wong, Stephanie; Wang, Jessica K.; Ouyang, Yong; He, Peng; Su, Yapeng; Casellas, Rafael; Baltimore, David (2018-04-26). "Epigenetic silencing of miR-125b is required for normal B-cell development". Blood. 131 (17): 1920–1930. doi:10.1182/blood-2018-01-824540. ISSN 0006-4971. PMC 5921965. PMID 29555645.
  7. ^ Mehta, Arnav; Baltimore, David (May 2016). "MicroRNAs as regulatory elements in immune system logic". Nature Reviews Immunology. 16 (5): 279–294. doi:10.1038/nri.2016.40. ISSN 1474-1733. PMID 27121651. S2CID 7229814.
  8. ^ Rodriguez, Antony; Griffiths-Jones, Sam; Ashurst, Jennifer L.; Bradley, Allan (2004-09-13). "Identification of Mammalian microRNA Host Genes and Transcription Units". Genome Research. 14 (10a): 1902–1910. doi:10.1101/gr.2722704. ISSN 1088-9051. PMC 524413. PMID 15364901.
  9. ^ Pogue, A.I.; Cui, J.G.; Li, Y.Y.; Zhao, Y.; Culicchia, F.; Lukiw, W.J. (May 2010). "Micro RNA-125b (miRNA-125b) function in astrogliosis and glial cell proliferation". Neuroscience Letters. 476 (1): 18–22. doi:10.1016/j.neulet.2010.03.054. PMID 20347935. S2CID 2420881.
  10. ^ Le, Minh T. N.; Xie, Huangming; Zhou, Beiyan; Chia, Poh Hui; Rizk, Pamela; Um, Moonkyoung; Udolph, Gerald; Yang, Henry; Lim, Bing; Lodish, Harvey F. (October 2009). "MicroRNA-125b Promotes Neuronal Differentiation in Human Cells by Repressing Multiple Targets". Molecular and Cellular Biology. 29 (19): 5290–5305. doi:10.1128/mcb.01694-08. ISSN 0270-7306. PMC 2747988. PMID 19635812.
  11. ^ a b Goljanek-Whysall, Katarzyna; Sweetman, Dylan; Münsterberg, Andrea E. (2012-08-01). "microRNAs in skeletal muscle differentiation and disease". Clinical Science. 123 (11): 611–625. doi:10.1042/cs20110634. ISSN 0143-5221. PMID 22888971.
  12. ^ Qiu, Jiaying; Zhu, Jianwei; Zhang, Ru; Liang, Wenpeng; Ma, Wenjing; Zhang, Qiuyu; Huang, Ziwei; Ding, Fei; Sun, Hualin (September 2019). "miR-125b-5p targeting TRAF6 relieves skeletal muscle atrophy induced by fasting or denervation". Annals of Translational Medicine. 7 (18): 456. doi:10.21037/atm.2019.08.39. ISSN 2305-5839. PMC 6803201. PMID 31700892.
  13. ^ Wojtowicz, Edyta E.; Lechman, Eric R.; Hermans, Karin G.; Schoof, Erwin M.; Wienholds, Erno; Isserlin, Ruth; van Veelen, Peter A.; Broekhuis, Mathilde J.C.; Janssen, George M.C.; Trotman-Grant, Aaron; Dobson, Stephanie M. (September 2016). "Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors". Cell Stem Cell. 19 (3): 383–396. doi:10.1016/j.stem.2016.06.008. PMC 5500905. PMID 27424784.
  14. ^ a b Guo, S.; Lu, J.; Schlanger, R.; Zhang, H.; Wang, J. Y.; Fox, M. C.; Purton, L. E.; Fleming, H. H.; Cobb, B.; Merkenschlager, M.; Golub, T. R. (2010-08-10). "MicroRNA miR-125a controls hematopoietic stem cell number". Proceedings of the National Academy of Sciences. 107 (32): 14229–14234. Bibcode:2010PNAS..10714229G. doi:10.1073/pnas.0913574107. ISSN 0027-8424. PMC 2922532. PMID 20616003.
  15. ^ a b c Shaham, L; Binder, V; Gefen, N; Borkhardt, A; Izraeli, S (September 2012). "MiR-125 in normal and malignant hematopoiesis". Leukemia. 26 (9): 2011–2018. doi:10.1038/leu.2012.90. ISSN 0887-6924. PMID 22456625. S2CID 30128839.
  16. ^ Emmrich, Stephan; Rasche, Mareike; Schöning, Jennifer; Reimer, Christina; Keihani, Sarva; Maroz, Aliaksandra; Xie, Ying; Li, Zhe; Schambach, Axel; Reinhardt, Dirk; Klusmann, Jan-Henning (2014-04-15). "miR-99a/100~125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling". Genes & Development. 28 (8): 858–874. doi:10.1101/gad.233791.113. ISSN 0890-9369. PMC 4003278. PMID 24736844.
  17. ^ Rossi, Riccardo L; Rossetti, Grazisa; Wenandy, Lynn; Curti, Serena; Ripamonti, Anna; Bonnal, Raoul J P; Birolo, Roberto Sciarretta; Moro, Monica; Crosti, Maria C; Gruarin, Paola; Maglie, Stefano (August 2011). "Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4+ T cells by the microRNA miR-125b". Nature Immunology. 12 (8): 796–803. doi:10.1038/ni.2057. ISSN 1529-2908. PMID 21706005. S2CID 205364249.
  18. ^ Chaudhuri, Aadel A.; So, Alex Yick-Lun; Sinha, Nikita; Gibson, William S. J.; Taganov, Konstantin D.; O’Connell, Ryan M.; Baltimore, David (2011-11-15). "MicroRNA-125b Potentiates Macrophage Activation". The Journal of Immunology. 187 (10): 5062–5068. doi:10.4049/jimmunol.1102001. ISSN 0022-1767. PMC 3208133. PMID 22003200.
  19. ^ a b c d e f Sun, Yu-Meng; Lin, Kang-Yu; Chen, Yue-Qin (December 2013). "Diverse functions of miR-125 family in different cell contexts". Journal of Hematology & Oncology. 6 (1): 6. doi:10.1186/1756-8722-6-6. ISSN 1756-8722. PMC 3566921. PMID 23321005.
  20. ^ Staedel, Cathy; Darfeuille, Fabien (September 2013). "MicroRNAs and bacterial infection: MicroRNAs and bacterial infection". Cellular Microbiology. 15 (9): 1496–1507. doi:10.1111/cmi.12159. PMID 23795564. S2CID 24746743.
  21. ^ Liu, Kai; Zhang, Yingang; Liu, Liang; Yuan, Qiling (January 2019). "miR-125 regulates PI3K/Akt/mTOR signaling pathway in rheumatoid arthritis rats via PARP2". Bioscience Reports. 39 (1). doi:10.1042/bsr20180890. ISSN 0144-8463. PMC 6328865. PMID 30541899.
  22. ^ Cui, Fang; Li, Xiuli; Zhu, Xiangyu; Huang, Lili; Huang, Yongfang; Mao, Caiying; Yan, Qi; Zhu, Jianhong; Zhao, Wenxia; Shi, Hong (2012). "MiR-125b Inhibits Tumor Growth and Promotes Apoptosis of Cervical Cancer Cells by Targeting Phosphoinositide 3-Kinase Catalytic Subunit Delta". Cellular Physiology and Biochemistry. 30 (5): 1310–1318. doi:10.1159/000343320. ISSN 1421-9778. PMID 23160634. S2CID 36846464.
  23. ^ Naidu, Srivatsava; Shi, Lei; Magee, Peter; Middleton, Justin D.; Laganá, Alessandro; Sahoo, Sudhakar; Leong, Hui Sun; Galvin, Melanie; Frese, Kristopher; Dive, Caroline; Guzzardo, Vincenza (December 2017). "PDGFR-modulated miR-23b cluster and miR-125a-5p suppress lung tumorigenesis by targeting multiple components of KRAS and NF-kB pathways". Scientific Reports. 7 (1): 15441. Bibcode:2017NatSR...715441N. doi:10.1038/s41598-017-14843-6. ISSN 2045-2322. PMC 5684387. PMID 29133857.
  24. ^ Dai, Jun; Wang, Jinyu; Yang, Lili; Xiao, Ying; Ruan, Qiurong (November 2015). "miR-125a regulates angiogenesis of gastric cancer by targeting vascular endothelial growth factor A". International Journal of Oncology. 47 (5): 1801–1810. doi:10.3892/ijo.2015.3171. ISSN 1019-6439. PMID 26398444.
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