| miR-203 | |
|---|---|
| miR-203 microRNA secondary structure and sequence conservation | |
| Identifiers | |
| Symbol | mir-203 |
| Rfam | RF00696 |
| miRBase family | MIPF0000108 |
| Entrez | 406986 |
| HUGO | 31581 |
| OMIM | 611899 |
| Other data | |
| RNA type | microRNA |
| Domain(s) | Eukaryota; Euteleostomi |
In molecular biology miR-203 is a short non-coding RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms, such as translational repression and Argonaute-catalyzed messenger RNA cleavage.[1][2] miR-203 has been identified as a skin-specific microRNA, and it forms an expression gradient that defines the boundary between proliferative epidermal basal progenitors and terminally differentiating suprabasal cells.[3] It has also been found upregulated in psoriasis[4] and differentially expressed in some types of cancer.[5][6]
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MicroRNAs are short (20-22nt), non-coding RNA molecules involved in the regulation of messenger RNAs (mRNAs) by pairing with their 3’ UTR and affecting their stability[4] or directing their silencing or degradation.[1] MicroRNAs are likely to play roles in most cellular processes, including proliferation, development, differentiation and apoptosis.[5] They are located in intergenic and intragenic regions, and are transcribed as pri-miRNA by RNA polymerase II or RNA polymerase III.[4] They then undergo extensive post-transcriptional modifications, starting with the processing of the pri-miRNA in the nucleus to generate a 70-100 nt long pre-miRNA by ribonucleases Drosha and DGCR8. This pre-miRNA is then transported out of the nucleus by Exportin-5, and is then further processed by Dicer into a mature 18-25 nt long double stranded microRNA.[7] The guide strand of the miRNA is then loaded into RNA-induced silencing complex (RISC)[7] and is then able to pair with its target. The passenger strand, denoted by a star, is commonly degraded, though this is not always the case.[8]
MiR-203 is a microRNA that is specifically expressed in keratinocytes (the most abundant cell type in the epidermis) and in normal conditions promotes epidermal differentiation by restricting proliferative potential and inducing cell-cycle exit.[3] It does so by repressing p63, an essential regulator of stem cell maintenance in epithelial stratified tissues.[3] Other proposed targets are suppresor of cytokine signaling 3 (SOCS3) and ABL1.
As is the case with many other microRNAs, miR-203 expression has been found dysregulated in several malignancies, including psoriasis, rheumatoid arthritis and carcinogenesis.[5][9][10][11][12]
In mice, miR-203 is located in chromosome 12, within a fragile 7-Mb region that is lost is some hematopoietic malignancies. This region encodes 52 mature miRNAs, ~12% of the mammalian miRNA genome. In humans, this region is conserved and located intergenically in 14q32.[11]
This microRNA was predicted using computational tools by comparison to mouse and tiger blowfish sequences.[13] It has been validated in zebrafish and its expression confirmed in humans by cloning and sequencing, where it was found in the outer layer of epidermis.[14]
miR-203 has one validated target, p63, conserved across vertebrate lineages. p63 is an essential regulator of stem cell maintenance in stratified epithelial tissues. Yi et al.[3] confirmed p63 as a target of miR-203. They showed that miR-203 expression is conspicuous in terminally differentiating epithelial cells, but is not present on their proliferative progenitor compartments, and shows a mutually exclusive pattern of expression with p63. They also report downregulation of proteins downstream of p63, suggesting a mechanistic method for inhibition of proliferative potential of epidermal stem cells.
There is some controversy as to whether suppressor of cytokine signaling 3 (SOCS3) is also targeted by miR-203. In their study, Lena et al. (2008)[12] showed that, despite bioinformatic alignment of miR-203 with SOCS3 3'UTR, the levels of SOCS3 transcripts increased in keratinocytes stimulated to differentiate in vitro, in parallel with miR-203. Then they exogenously expressed miR-203 in mouse keratinocytes and showed that SOCS3 is not repressed by miR-203.
In contrast, Wei et al. (2010)[15] validated SOCS3 as a target for miR-203. In their study, they introduced the SOCS3 3'UTR fragment encompassing the putative target site in a luciferase reporter vector, and they observed a significant decrease in luciferase activity when miR-203 was introduced compared to controls. They also generated a mutation in the binding site and reported restoration of luciferase activity, as well as mutually exclusive localization with miR-203. They concluded that SOCS3 is targeted by miR-203, and hypothesize that miR-203 regulation of SOCS3 and thus of STAT3 could have implications in keratinocyte functions.
Another putative target is ABL1, which is found activated in hematopoietic malignancies where miR-203 is epigenetically silenced by hypermethylation.[11]
Yi et al. showed that in mice, the expression of miR-203 is significantly upregulated between E13.5 and E15.5, suggesting that it may be absent from multipotent progenitors of single-layered epidermis, but is induced upon stratification and differentiation.[3] It also was expressed at high levels in differentiating cells such as hair follicles, epidermis and sebaceous glands.
Wei et al.[15] demonstrated that in humans, miR-203 expression is first detectable at 17 weeks gestation in the suprabasal layers of epidermis, and this localization was conserved in the adult skin. When miR-203 is expressed prematurely, basal cells diminish their proliferative potential; and when it is absent, proliferation is no longer restricted to the basal layer of epidermis.[16]
miR-203 has been found overexpressed in pancreatic adenocarcinoma and shows correlation with poor prognosis in patients that had undergone pancreatectomy, and has been suggested as a new prognostic marker for this disease.[5][9] Also, miR-203 has been identified as target of human papillomavirus (HPV) protein E7,[6] which causes its downregulation and thus de-repression of p63 and its downstream targets, ensuring proliferative potential on the host cell, required for the virus to replicate. High levels of miR-203 are inhibitory of HPV amplification.[6]
miR-203 has also been proposed as a tumour-suppresive microRNA in hepatocellular carcinoma (HCC) and hematopoietic malignancies. In their study, Furuta et al.[10] found miR-203, along with miR-124, epigenetically silenced in primary HCC tumours compared with non-tumorous liver tissues. Also, expression of miR-203 in HCC cells lacking their expression inhibited cell growth and downregulated a set of other possible targets. Bueno et al.[11] also found silencing of miR-203 in some leukemias, as well as an inverse correlation between miR-203 and ABL1 levels (sometimes expressed as the BCR-ABL1 fusion protein). Supporting its role as a tumour suppressor, it has also been found upregulated upon UVC irradiation in the squamous cell carcinoma lines, suggesting a connection between miR-203 and the activation of the apoptotic program.[12]
Sonkoly et al.[17] identified miR-203, along with miR-146a, miR-21, and miR-125b; as a psoriasis-specific microRNA when compared with healthy human skin or atopic eczema. They also observed downregulation of SOCS3 concurrently with upregulation of miR-203 in psoriatic plaques, potentially having an effect in inflammatory responses.
Stanczyk et al.[18] found overexpression of miR-203 in rheumatoid arthritis synovial fibroblasts (RASFs) compared to healthy or osteoarthritis samples; and inforced expression of miR-203 led to higher levels of MMP-1 and IL-6 and thus contributed to the activated phenotype of RASFs. MiR-203 regulation was found to be methylation-dependent.
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