MiR-138 explained

miR-138
Symbol:miR-138
Rfam:RF00671
Mirbase:MI0000476
Mirbase Family:MIPF0000075
Rna Type:miRNA
Tax Domain:Animalia
Entrezgene:406929
Hgncid:31524
Chromosome:3
Arm:p

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

The presence of miR-138 has been detected experimentally in humans (Homo sapiens)[4] [5] and in different animals including house mouse (Mus musculus),[6] [7] [8] [9] brown rat (Rattus norvegicus),[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] chimpanzee (Pan troglodytes),[32] Tetraodon nigroviridis and western clawed frog (Xenopus tropicalis).

Genomic location

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

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.

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

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.

HIF-1a: 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-ABL and CCND3: 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]
  • ALDH1A2 and CSPG2: 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.
  • 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]

    • Further reading

    Notes and References

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