Examples of miRNAs associated with AML that change expression level
1. Introduction
Large-scale analysis of total genome transcripts (transcriptome) in organisms including human and mouse has revealed that many RNAs are transcribed from genomic regions that encode no proteins (referred to as ncRNA) (1-5). Among such ncRNAs, microRNAs (miRNAs), small molecule RNAs 18-28 bases long, have been extensively studied over the past decade, and a gene regulatory system called “RNA silencing” has been revealed. In humans, more than 400 miRNAs are known to regulate at least one-third of protein-encoding genes (6-10). Most miRNAs are generated by processing of long miRNA precursors (pri-miRNAs) (6, 9). Pri-miRNAs are transcribed by RNA polymerase II and 5’ cap structures and poly A tails are added, similarly to protein-encoding mRNAs. Pri-miRNAs are further processed in the nucleus into pre-miRNAs with an approximately 70 base hairpin structure and are then exported to the cytoplasm. pre-miRNAs are finally processed into mature miRNAs by the enzyme, Dicer. It is noteworthy that miRNAs are sometimes encoded in the introns of other genes. A mature miRNA is incorporated into the RNA-induced silencing complex to act on its target mRNA. Broadly speaking, miRNAs can act on mRNAs in two ways. If there is limited homology between an miRNA and a target mRNA, the miRNA suppresses translation of the mRNA. However, if the miRNA has complete or nearly complete homology with a target mRNA, the mRNA is rapidly degraded. In animal cells, the former scenario usually occurs (7, 10-12). Many miRNAs have been reported to be associated with tumors, including AML and glioma; however, it is still unclear how predominant miRNAs are in tumorigenesis.
Relatively large ncRNAs of over several hundred bases, which are longer than pri-miRNAs whose length is usually 200-300 bases, are called long-chain non-coding RNAs (lncRNAs). Despite their somewhat unclear definition and their largely undetermined functions (13), the public databases for lncRNAs, for example, lncRNAdb (http://www.lncrnadb.org/) (14) or NONCODE (http://www.noncode.org) (15), contain several hundred mammalian lncRNAs, including more than 100 from human (16). The RNAs included are heterologous; some localize in the nucleus to form certain structures, others interact with chromatin modifying enzymes such as p300, while others function in the cytoplasm (Fig. 1).
Both miRNAs and lncRNAs are physiologically important in many biological processes, including development and cell differentiation. Their association with disease, especially cancers, is of great interest (5). Association of miRNAs with various tumors, including different types of leukemia (Table 1) and glioma (Table 2), has been demonstrated. They sometimes act as tumor-promoting factors and sometimes as tumor suppressors. Expression of many lncRNAs, including
Name | Loci | Name | Loci |
let-7b | let-7 | ||
let-7e | let-7b | ||
miR-10a | miR-9* | ||
miR-10b | miR-15a | ||
miR-27a | miR-15b | ||
miR-30d | miR-16 | ||
miR-126 | miR-19a | ||
miR-129-5p | miR-20a | ||
miR-130b | miR-26a | ||
miR-142-5p | miR-29a | ||
miR-155 | miR-29b | ||
miR-181a | miR-29c | ||
miR-181b | miR-30a-3p | ||
miR-181c | miR-34b | ||
miR-181d | miR-34c | ||
miR-195 | miR-124 | ||
miR-221 | miR-128-1 | ||
miR-223 | miR-145 | ||
miR-221/222 | miR-147 | ||
miR-324-5p | miR-148a | ||
miR-326 | miR-151 | ||
miR-328 | miR-181a | ||
miR-331 | miR-181b | ||
miR-340 | miR-182 | ||
miR-374 | miR-184 | ||
miR-424 | miR-194 | ||
miR-196a | |||
miR-196a | |||
miR-199a | |||
miR-204 | |||
miR-219-5p | |||
miR-220a | |||
miR-302b* | |||
miR-302d | |||
miR-320 | |||
miR-320 | |||
miR-325 | |||
Name | Genetic Locus | Name | Genetic Locus |
miR-9* | let-7 family | ||
miR-10a* | miR-7 | ||
miR-10b | miR-15b | ||
miR-17/92 cluster | miR-17 | ||
miR-21 | miR-26b | ||
miR-25 | miR-29b | ||
miR-26a | miR-34a | ||
miR-93 | miR-101 | ||
miR-125b | miR-106a | ||
miR-182 | miR-124 | ||
miR-195 | miR-125a | ||
miR-196a | miR-128 | ||
miR-196b | miR-137 | ||
miR-221/222 | miR-146b/146b-5p | ||
miR-296 | miR-153 | ||
miR-381 | miR-181 | ||
miR-455-3p | miR-184 | ||
miR-486 | miR-195 | ||
miR-199b-5p | |||
miR-218 | |||
miR-326 | |||
miR-451 | |||
Name | Alias | Mouse Homolog | Genetic Locus | Product Length (bp) | Tumor | Function | Refs | ||
NA | Wilms’ tumor | NA | (59) | ||||||
200 | Breast cancer | Regulation of proteinbiosynthesis | (70) | ||||||
NA | 2051 | Multiplecancers | Decoy of mRNA | (71) | |||||
2364 | Multiple cancers | Epigenetic silencing of HOXD gene through histoneH3K27 methylation | (72) | ||||||
NA | 500 | Hepatocellular carcinoma | Post-transcriptional regulation | (73) | |||||
2091 | Wilms' tumor | NA | (74) | ||||||
NA | 5178 | Prostate cancer | Decoy of miRNA | (75) | |||||
833 | Many tumor cell lines | Activation of proto-oncogene | (76) | ||||||
8708 | Multiple cancer | Control of RNA procession | (19, 77) | ||||||
1060 | Many tumor cell lines | Activation of proto-oncogene | (76) | ||||||
NA | 3735 | Prostate cancer | NA | (78) | |||||
NA | 1603 | Prostate cancer | NA | (79) | |||||
NA | "/>12756 | Prostate cancer | NA | (80) | |||||
1955 | Breast cancer | Activation of nuclear receptors | (81) | ||||||
451 | Multiple cancer | Telomere template | (82) | ||||||
NA | 1591 | Bladder cancer | Regulation of cell cycle | (83) | |||||
NA | 1333 | Wilms' tumorAML | Downregulation of WT1, tumor suppressor | (84) | |||||
19271 | Multiple cancers | Xinactivation | (56, 85) | ||||||
NA | 2807 | Papillary thyroid carcinoma | NA | (24) | |||||
NA | 944 | Prostate cancer, breast cancer, melanoma, andother tumors | Regulation of epigenetic transcriptional repression | (58) | |||||
NA | NA | Osteosarcoma | NA | (25) | |||||
2768 | Chroniclymphocytic leukemia | pri-miRNA for miR15a and miR16 | (86) | ||||||
651 | Breast cancer | Decoy of glucocorticoid receptor | (87) | ||||||
2322 | Wilms' tumor | Epigenetic regulation through DNA methylation | (88) | ||||||
91671 | Embryonal cancer associated with Beckwith-Wiedemann syndrome | Epigenetic imprinting through H3K27 methylation | (57) | ||||||
NA | NA | Osteosarcoma | NA | (25) | |||||
1595 | Glioma, pituitary adenoma andother tumor | Regulation of p53 target proteins | (89) | ||||||
NA | 131 | Neuroblastoma | Induction the appearance of neuronal-like properties | (18) | |||||
19144 | Multiple cancer | RNA protein binding, MDM3 | (90) | ||||||
NA | 3932 | Prostate cancer | Decoy for PTEN-targeting miRNAs | (75) | |||||
267 | Leukemia and lymphoma | Mitochondrial RNA processing endoribonuclease, hTERT-dependent | (91) | ||||||
telomere repeats | NA | Many cancer cell lines | Interaction with the TRF1 | (92) | |||||
NA | 100 | AML, papillary thyroid cancer | Regulation of RNA dependent protein kinase (pPKR) | (93) | |||||
1020 | Breast cancer | NA | (94) |
2. Genetic abnormality observed in acute myeloid leukemia (AML)
AML, which comprises approximately 25% of hematopoietic malignancies, has heterogeneous clinical features and variable responses to contemporary therapy (26). Genetic alterations are often observed in AML cells and the clinical heterogeneity of the disease is considered to reflect the genetic diversity of these cells (27, 28). It is very important to study the genetic mutations in AML cells to fully understand the cause of the disease. However, genetic lesion(s) responsible for AML, such as the loss or gain of a certain gene, have not yet been fully elucidated. Indeed, the complex features of AML suggest that the genetic cause of this disease is multifactorial (29). Several protein-encoding genes have been identified that are useful for indicating the prognosis of the disease (30-32). These include
3. AML and CCDC26
In HL-60 cells derived from AML, a small part of chromosome 8 is excised and amplified as an extrachromosomal element, or double minute chromosome (dmin). Dmin is a cytogenetic abnormality infrequently observed in AML. The dmin of HL-60 cells consists of several repeats of an amplification unit (referred as amplicon) of about 2 million base pairs. The amplicon, which is derived from several areas of an approximately 4.6 million base pair region of chromosome
A common change occurs at the
A comprehensive genome-wide study of a group of childhood AML patients revealed that
Originally,
4. Glioma and CCDC26
Primary brain tumor (PBT) is a disease with an incidence of 12 in 100,000 per year. Glioma accounts for a major part of PBT, and contains cases with different grades of malignancy, namely (I) benign glioma, (II) diffuse astrocytoma, (III) anaplastic astrocytoma and (IV) glioblastoma (43). Although many genetic abnormalities have been reported in gliomas, a single critical lesion responsible for tumorigenesis has not been found. Among these abnormalities, mutations occur in genes for DNA repair enzymes, including
The Gene Expression Omnibus database (GEO; http://www.ncbi.nlm.nih.gov/geo/) (49) contains data showing altered
5. Overview of the CCDC26 genetic locus
As described in the previous section, all SNPs associated with glioma, and a retrovirus insertion site where virus insertion makes AML cells resistant to retinoic acid (42) are located in the intron of
A short putative ORF encoding a protein or with a length of 109 amino acids is present in the
Because of the considerable length of the
highly conserved among mammals, suggesting that function is encoded. Also, expressed sequence tags other than known spliced
6. Hypothetical function of CCDC26 as a non-coding RNA
Although many ncRNAs are registered in databases, only a few have clearly demonstrated functions and detailed mechanisms of action.
Within the CCDC26 intronic region, there are some long regions (>10 kb) that are actively transcribed in leukemia cells (Fig. 3a). They seem to be too long for pri-miRNAs but could encode lncRNAs. Indeed, active transcription occurs in the
7. Future perspectives
The size of the
8. Conclusion
As a conclusion, the
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