From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
Mir-138 SS.png
Conserved secondary structure of miR-138 prescursor
miRBase familyMIPF0000075
Other data
RNA typemiRNA
LocusChr. 3 p
PDB structuresPDBe

miR-138 is a family of microRNA precursors found in animals, including humans.[1] MicroRNAs are typically transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide product.[2] The excised region or, mature product, of the miR-138 precursor is the microRNA mir-138.

miR-138 has been used as an example of the post-transcriptional regulation of miRNA, due to the finding that while the precursor is expressed ubiquitously, the mature product is found only in specific cell types.[3]

Species distribution[edit]

The presence of miR-138 has been detected experimentally in humans (Homo sapiens)[1][4][5] and in different animals including house mouse (Mus musculus),[1][3][4][6][7][8][9] brown rat (Rattus norvegicus),[1][7][10][11][12] platypus (Ornithorhynchus anatinus),[13] Carolina anole(Anolis carolinensis),[14] cattle (Bos taurus),[15][16] common carp (Cyprinus carpio),[17] dog (Canis familiaris),[18] Chinese hamster (Cricetulus griseus),[19] zebrafish (Danio rerio),[20] red junglefowl (Gallus gallus),[21] western gorilla (Gorilla gorilla),[22] gray short-tailed opossum (Monodelphis domestica),[23] Oryzias latipes,[24] sea lamprey (Petromyzon marinus),[25] Tasmanian devil (Sarcophilus harrisii),[26] wild boar (Sus scrofa)[27] and zebra finch (Taeniopygia guttata).[28]

It is also predicted computationally that the miR-138 gene exists in the genome of other animals including horse (Equus caballus),[29] rhesus macaque (Macaca mulatta),[30] takifugu rubripes (Fugu rubripes), Bornean orangutan (Pongo pygmaeus),[31] common chimpanzee (Pan troglodytes),[32] Tetraodon nigroviridis and western clawed frog (Xenopus tropicalis).

Genomic location[edit]

In human genome, there are two miR-138 associated genes and they are not located in any cluster. More precisely, the miR-138-1 gene is in region 5 at 3p21.3[33] and miR-138-2 is located on chromosome 16 (16q13).[34]

Pattern of expression[edit]

In adult mice, miR-138 is only expressed in brain tissue. Its expression is not uniform throughout the brain but restricted to distinct neuronal populations. On the contrary, its precursor, pre-miR-138-2, is ubiquitously expressed throughout all tissues, which suggests that the expression of miRNAs can be regulated at the post-transcription level.[3]

In the zebrafish, miR-138 is expressed in specific domains in the heart and is required to establish appropriate chamber-specific gene expression patterns.[35]

Targets and function[edit]

Since the identification of miR-138, a number of targets have been found and some of them have been verified experimentally. It has been proven that miR-138 is involved in different pathways. Furthermore, it is in relation with various types of cancer.

Hypoxia-inducible factor-1alpha (HIF-1a), one of the key regulators in cancer cells, has been shown to be one target of miR-138.[36]
VIM, ZEB2, EZH2 and head and neck cancers
Downregulation of miR-138 has been reported in several types of cancers, including HNSCC(head and neck squamous cell carcinoma). It is suggested that miR-138 is a multi-functional molecular regulator and plays major roles in EMT (epithelial-mesenchymal transition) and in HNSCC progression. A number of miR-138 target genes have been identified to be associated with EMT, including VIM (vimentin), ZEB2 (zinc finger E-box-binding homeobox 2) and EZH2 (enhancer of zeste homologue 2).[37]
CCND1 and nasopharyngeal carcinoma
miR-138 is commonly underexpressed in nasopharyngeal carcinoma (NPC) specimens and NPC cell lines. Cyclin D1 (CCND1), which is widely upregulated in NPC tumors, is found as a direct target of miR-138. Therefore, miR-138 might be a tumor suppressor in NPC, which is exerted partially by inhibiting CCND1 expression.[38]
BCR (breakpoint cluster region)-ABL (c-abl oncogene 1, non-receptor tyrosine kinase)/GATA1/miR-138 mini circuitry contributes to the leukemogenesis of chronic myeloid leukemia (CML). ABL and BCR-ABL are the target genes of miR-138, which binds to the coding region instead of three prime untranslated region (3'UTR). miR-138 can negatively regulate another gene CCND3 via binding to its 3'-UTR. The expression of miR-138 is activated by GATA1, which in turn is repressed by BCR-ABL. Therefore, miR-138, by virtue of a BCR-ABL/GATA1/miR-138 circuitry, is a tumor suppressor miRNA implicated in the pathogenesis of CML and its clinical response to imatinib.[39]
H2AX and DNA damage repair
mir-138 is linked with DNA damage repair. It can directly target the histone H2AX 3'UTR, reduce histone H2AX expression and induce chromosomal instability after DNA damage.[40]
In zebrafish, the mature form of miR-138 regulates gene expression influencing cardiac development. miR-138 helps establish discrete domains of gene expression during cardiac morphogenesis by targeting multiple members of a common pathway. It has been experimentally verified that miR-138 can negatively regulate aldh1a2, encoding retinoic acid (RA) dehydrogenase (Raldh2), by targeting the binding site in the 3'UTR of its mRNA. Another putative target of miR-138 is cspg2.[35]
Regulation of sleep
In rats, miR-138, let-7b, and miR-125a are expressed at different times and in different structures in the brain and likely play a role in the regulation of sleep.[41]
Brain cancer
miR-138 has been found to be significantly linked with the formation and growth of Gliomas, from Cancerous Stem Cells (CSC). In vitro inhibition of miR-138 prevents tumour sphere formation. Furthermore, its high expression in Glioma makes it a potential biomarker for CSC.[42]
Rhoc, ROCK2 and Tongue cancer
Tumour metastasis concerning the Tongue Squamous Cell Carcinoma (TSCC) can be regulated via the expression of 2 key genes in Rho GTPase signaling pathway : RhoC and ROCK2 (Rho-associated protein kinase 2). Thus, by targeting the 3' untranslated region of those genes, mir-138 is able to reduce their expression and by this mean, to destroy TSCC ability migrate and invade.[43]


  1. ^ a b c d Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, et al. (Jun 2007). "A mammalian microRNA expression atlas based on small RNA library sequencing". Cell. 129 (7): 1401–14. doi:10.1016/j.cell.2007.04.040. PMC 2681231. PMID 17604727.
  2. ^ Ambros V (Dec 2001). "microRNAs: tiny regulators with great potential". Cell. 107 (7): 823–6. doi:10.1016/S0092-8674(01)00616-X. PMID 11779458.
  3. ^ a b c Obernosterer G, Leuschner PJ, Alenius M, Martinez J (Jul 2006). "Post-transcriptional regulation of microRNA expression". RNA. 12 (7): 1161–7. doi:10.1261/rna.2322506. PMC 1484437. PMID 16738409.
  4. ^ a b Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T (Apr 2002). "Identification of tissue-specific microRNAs from mouse". Current Biology. 12 (9): 735–9. doi:10.1016/s0960-9822(02)00809-6. PMID 12007417.
  5. ^ Lui WO, Pourmand N, Patterson BK, Fire A (Jul 2007). "Patterns of known and novel small RNAs in human cervical cancer". Cancer Research. 67 (13): 6031–43. doi:10.1158/0008-5472.can-06-0561. PMID 17616659.
  6. ^ Weber MJ (Jan 2005). "New human and mouse microRNA genes found by homology search". The FEBS Journal. 272 (1): 59–73. doi:10.1111/j.1432-1033.2004.04389.x. PMID 15634332.
  7. ^ a b Kim J, Krichevsky A, Grad Y, Hayes GD, Kosik KS, Church GM, Ruvkun G (Jan 2004). "Identification of many microRNAs that copurify with polyribosomes in mammalian neurons". Proceedings of the National Academy of Sciences of the United States of America. 101 (1): 360–5. doi:10.1073/pnas.2333854100. PMC 314190. PMID 14691248.
  8. ^ Ahn HW, Morin RD, Zhao H, Harris RA, Coarfa C, Chen ZJ, Milosavljevic A, Marra MA, Rajkovic A (Jul 2010). "MicroRNA transcriptome in the newborn mouse ovaries determined by massive parallel sequencing". Molecular Human Reproduction. 16 (7): 463–71. doi:10.1093/molehr/gaq017. PMC 2882868. PMID 20215419.
  9. ^ Chiang HR, Schoenfeld LW, Ruby JG, Auyeung VC, Spies N, Baek D, Johnston WK, Russ C, Luo S, Babiarz JE, Blelloch R, Schroth GP, Nusbaum C, Bartel DP (May 2010). "Mammalian microRNAs: experimental evaluation of novel and previously annotated genes". Genes & Development. 24 (10): 992–1009. doi:10.1101/gad.1884710. PMC 2867214. PMID 20413612.
  10. ^ Miska EA, Alvarez-Saavedra E, Townsend M, Yoshii A, Sestan N, Rakic P, Constantine-Paton M, Horvitz HR (2004). "Microarray analysis of microRNA expression in the developing mammalian brain". Genome Biology. 5 (9): R68. doi:10.1186/gb-2004-5-9-r68. PMC 522875. PMID 15345052.
  11. ^ He X, Zhang Q, Liu Y, Pan X (Sep 2007). "Cloning and identification of novel microRNAs from rat hippocampus". Acta Biochimica et Biophysica Sinica. 39 (9): 708–14. doi:10.1111/j.1745-7270.2007.00324.x. PMID 17805466.
  12. ^ Linsen SE, de Wit E, de Bruijn E, Cuppen E (19 April 2010). "Small RNA expression and strain specificity in the rat". BMC Genomics. 11 (1): 249. doi:10.1186/1471-2164-11-249. PMC 2864251. PMID 20403161.
  13. ^ Murchison EP, Kheradpour P, Sachidanandam R, Smith C, Hodges E, Xuan Z, Kellis M, Grützner F, Stark A, Hannon GJ (Jun 2008). "Conservation of small RNA pathways in platypus". Genome Research. 18 (6): 995–1004. doi:10.1101/gr.073056.107. PMC 2413167. PMID 18463306.
  14. ^ Lyson TR, Sperling EA, Heimberg AM, Gauthier JA, King BL, Peterson KJ (Feb 2012). "MicroRNAs support a turtle + lizard clade". Biology Letters. 8 (1): 104–7. doi:10.1098/rsbl.2011.0477. PMC 3259949. PMID 21775315.
  15. ^ Coutinho LL, Matukumalli LK, Sonstegard TS, Van Tassell CP, Gasbarre LC, Capuco AV, Smith TP (Mar 2007). "Discovery and profiling of bovine microRNAs from immune-related and embryonic tissues". Physiological Genomics. 29 (1): 35–43. doi:10.1152/physiolgenomics.00081.2006. PMID 17105755.
  16. ^ Tesfaye D, Worku D, Rings F, Phatsara C, Tholen E, Schellander K, Hoelker M (Jul 2009). "Identification and expression profiling of microRNAs during bovine oocyte maturation using heterologous approach". Molecular Reproduction and Development. 76 (7): 665–77. doi:10.1002/mrd.21005. PMID 19170227.
  17. ^ Yan X, Ding L, Li Y, Zhang X, Liang Y, Sun X, Teng CB (2012). "Identification and profiling of microRNAs from skeletal muscle of the common carp". PLOS ONE. 7 (1): e30925. doi:10.1371/journal.pone.0030925. PMC 3267759. PMID 22303472.
  18. ^ Friedländer MR, Chen W, Adamidi C, Maaskola J, Einspanier R, Knespel S, Rajewsky N (Apr 2008). "Discovering microRNAs from deep sequencing data using miRDeep". Nature Biotechnology. 26 (4): 407–15. doi:10.1038/nbt1394. PMID 18392026.
  19. ^ Hackl M, Jakobi T, Blom J, Doppmeier D, Brinkrolf K, Szczepanowski R, Bernhart SH, Höner Zu Siederdissen C, Bort JA, Wieser M, Kunert R, Jeffs S, Hofacker IL, Goesmann A, Pühler A, Borth N, Grillari J (Apr 2011). "Next-generation sequencing of the Chinese hamster ovary microRNA transcriptome: Identification, annotation and profiling of microRNAs as targets for cellular engineering". Journal of Biotechnology. 153 (1–2): 62–75. doi:10.1016/j.jbiotec.2011.02.011. PMC 3119918. PMID 21392545.
  20. ^ Chen PY, Manninga H, Slanchev K, Chien M, Russo JJ, Ju J, Sheridan R, John B, Marks DS, Gaidatzis D, Sander C, Zavolan M, Tuschl T (Jun 2005). "The developmental miRNA profiles of zebrafish as determined by small RNA cloning". Genes & Development. 19 (11): 1288–93. doi:10.1101/gad.1310605. PMC 1142552. PMID 15937218.
  21. ^ International Chicken Genome Sequencing Consortium (Dec 2004). "Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution". Nature. 432 (7018): 695–716. doi:10.1038/nature03154. PMID 15592404.
  22. ^ Dannemann M, Nickel B, Lizano E, Burbano HA, Kelso J (27 March 2012). "Annotation of primate miRNAs by high throughput sequencing of small RNA libraries". BMC Genomics. 13 (1): 116. doi:10.1186/1471-2164-13-116. PMC 3328248. PMID 22453055.
  23. ^ Devor EJ, Samollow PB (January–February 2008). "In vitro and in silico annotation of conserved and nonconserved microRNAs in the genome of the marsupial Monodelphis domestica". The Journal of Heredity. 99 (1): 66–72. doi:10.1093/jhered/esm085. PMID 17965199.
  24. ^ Li SC, Chan WC, Ho MR, Tsai KW, Hu LY, Lai CH, Hsu CN, Hwang PP, Lin WC (2 December 2010). "Discovery and characterization of medaka miRNA genes by next generation sequencing platform". BMC Genomics. 11 Suppl 4 (Suppl 4): S8. doi:10.1186/1471-2164-11-s4-s8. PMC 3005926. PMID 21143817.
  25. ^ Heimberg AM, Cowper-Sal-lari R, Sémon M, Donoghue PC, Peterson KJ (Nov 2010). "microRNAs reveal the interrelationships of hagfish, lampreys, and gnathostomes and the nature of the ancestral vertebrate". Proceedings of the National Academy of Sciences of the United States of America. 107 (45): 19379–83. doi:10.1073/pnas.1010350107. PMC 2984222. PMID 20959416.
  26. ^ Murchison EP, Tovar C, Hsu A, Bender HS, Kheradpour P, Rebbeck CA, Obendorf D, Conlan C, Bahlo M, Blizzard CA, Pyecroft S, Kreiss A, Kellis M, Stark A, Harkins TT, Marshall Graves JA, Woods GM, Hannon GJ, Papenfuss AT (Jan 2010). "The Tasmanian devil transcriptome reveals Schwann cell origins of a clonally transmissible cancer". Science. 327 (5961): 84–7. doi:10.1126/science.1180616. PMC 2982769. PMID 20044575.
  27. ^ Li G, Li Y, Li X, Ning X, Li M, Yang G (May 2011). "MicroRNA identity and abundance in developing swine adipose tissue as determined by Solexa sequencing". Journal of Cellular Biochemistry. 112 (5): 1318–28. doi:10.1002/jcb.23045. PMID 21312241.
  28. ^ Warren WC, Clayton DF, Ellegren H, Arnold AP, Hillier LW, Künstner A, et al. (Apr 2010). "The genome of a songbird". Nature. 464 (7289): 757–62. doi:10.1038/nature08819. PMC 3187626. PMID 20360741.
  29. ^ Zhou M, Wang Q, Sun J, Li X, Xu L, Yang H, Shi H, Ning S, Chen L, Li Y, He T, Zheng Y (Aug 2009). "In silico detection and characteristics of novel microRNA genes in the Equus caballus genome using an integrated ab initio and comparative genomic approach". Genomics. 94 (2): 125–31. doi:10.1016/j.ygeno.2009.04.006. PMID 19406225.
  30. ^ Yue J, Sheng Y, Orwig KE (10 January 2008). "Identification of novel homologous microRNA genes in the rhesus macaque genome". BMC Genomics. 9 (1): 8. doi:10.1186/1471-2164-9-8. PMC 2254598. PMID 18186931.
  31. ^ Brameier M (9 March 2010). "Genome-wide comparative analysis of microRNAs in three non-human primates". BMC Research Notes. 3 (1): 64. doi:10.1186/1756-0500-3-64. PMC 2850348. PMID 20214803.
  32. ^ Baev V, Daskalova E, Minkov I (Feb 2009). "Computational identification of novel microRNA homologs in the chimpanzee genome". Computational Biology and Chemistry. 33 (1): 62–70. doi:10.1016/j.compbiolchem.2008.07.024. PMID 18760970.
  33. ^ Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM (Mar 2004). "Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers". Proceedings of the National Academy of Sciences of the United States of America. 101 (9): 2999–3004. doi:10.1073/pnas.0307323101. PMC 365734. PMID 14973191.
  34. ^ Liu X, Jiang L, Wang A, Yu J, Shi F, Zhou X (Dec 2009). "MicroRNA-138 suppresses invasion and promotes apoptosis in head and neck squamous cell carcinoma cell lines". Cancer Letters. 286 (2): 217–22. doi:10.1016/j.canlet.2009.05.030. PMC 2783372. PMID 19540661.
  35. ^ a b Morton SU, Scherz PJ, Cordes KR, Ivey KN, Stainier DY, Srivastava D (Nov 2008). "microRNA-138 modulates cardiac patterning during embryonic development". Proceedings of the National Academy of Sciences of the United States of America. 105 (46): 17830–5. doi:10.1073/pnas.0804673105. PMC 2582580. PMID 19004786.
  36. ^ Song T, Zhang X, Wang C, Wu Y, Cai W, Gao J, Hong B (2011). "MiR-138 suppresses expression of hypoxia-inducible factor 1α (HIF-1α) in clear cell renal cell carcinoma 786-O cells". Asian Pacific Journal of Cancer Prevention. 12 (5): 1307–11. PMID 21875287.
  37. ^ Liu X, Wang C, Chen Z, Jin Y, Wang Y, Kolokythas A, Dai Y, Zhou X (Nov 2011). "MicroRNA-138 suppresses epithelial-mesenchymal transition in squamous cell carcinoma cell lines". The Biochemical Journal. 440 (1): 23–31. doi:10.1042/BJ20111006. PMC 3331719. PMID 21770894.
  38. ^ Liu X, Lv XB, Wang XP, Sang Y, Xu S, Hu K, Wu M, Liang Y, Liu P, Tang J, Lu WH, Feng QS, Chen LZ, Qian CN, Bei JX, Kang T, Zeng YX (Jul 2012). "MiR-138 suppressed nasopharyngeal carcinoma growth and tumorigenesis by targeting the CCND1 oncogene". Cell Cycle. 11 (13): 2495–506. doi:10.4161/cc.20898. PMID 22739938.
  39. ^ Xu C, Fu H, Gao L, Wang L, Wang W, Li J, Li Y, Dou L, Gao X, Luo X, Jing Y, Chim CS, Zheng X, Yu L (Jan 2014). "BCR-ABL/GATA1/miR-138 mini circuitry contributes to the leukemogenesis of chronic myeloid leukemia". Oncogene. 33 (1): 44–54. doi:10.1038/onc.2012.557. PMID 23208504.
  40. ^ Wang Y, Huang JW, Li M, Cavenee WK, Mitchell PS, Zhou X, Tewari M, Furnari FB, Taniguchi T (Aug 2011). "MicroRNA-138 modulates DNA damage response by repressing histone H2AX expression". Molecular Cancer Research. 9 (8): 1100–11. doi:10.1158/1541-7786.MCR-11-0007. PMC 3157593. PMID 21693595.
  41. ^ Davis CJ, Clinton JM, Krueger JM (Dec 2012). "MicroRNA 138, let-7b, and 125a inhibitors differentially alter sleep and EEG delta-wave activity in rats". Journal of Applied Physiology. 113 (11): 1756–62. doi:10.1152/japplphysiol.00940.2012. PMC 3544506. PMID 23104698.
  42. ^ Chan XH, Nama S, Gopal F, Rizk P, Ramasamy S, Sundaram G, Ow GS, Ivshina AV, Tanavde V, Haybaeck J, Kuznetsov V, Sampath P (Sep 2012). "Targeting glioma stem cells by functional inhibition of a prosurvival oncomiR-138 in malignant gliomas". Cell Reports. 2 (3): 591–602. doi:10.1016/j.celrep.2012.07.012. PMID 22921398.
  43. ^ Jiang L, Liu X, Kolokythas A, Yu J, Wang A, Heidbreder CE, Shi F, Zhou X (Aug 2010). "Downregulation of the Rho GTPase signaling pathway is involved in the microRNA-138-mediated inhibition of cell migration and invasion in tongue squamous cell carcinoma". International Journal of Cancer. 127 (3): 505–12. doi:10.1002/ijc.25320. PMC 2885137. PMID 20232393.

Further reading[edit]

External links[edit]