| | Year | Hallmark |
| | 1993 | The first regulatory noncoding RNA was identified: lin-4
Two discoveries identified a novel mechanism of posttranscriptional gene regulation. The first miRNA lin-4 was described in 1993 as asmall temporal RNA (stRNA) in the laboratory of Ambros working with the nematode Caenorhabditis elegans. In this system, the transition from the first to the second larval stage fates requires the 22-nucleotide lin-4 RNA. The gene lin-4 encodes a small RNA, which is a non-protein-coding regulatory RNA molecule. In the same issue of cell, the group of Ruvkun reported the first miRNA target gene, the heterochronic gene lin-14, that is regulated by lin-4 mediating the temporal pattern formation in C. elegans. The sequence of lin-4 has antisense complementarity to lin-14 mRNA that encodes lin-14 protein [80, 81]. |
| | 2000 | The second small temporal RNA and the first in humans was identified: let-7
Seven years later the second regulatory stRNA, let-7, was discovered. The transition from late larval to adult cell fates in C. elegans requires the 21-nucleotide let-7 RNA. This stRNA negatively regulates, among others, lin-14 and lin-28 through RNA-RNA interactions with their 3′ untranslated regions. The sequential stage-specific expression of the lin-4 and let-7 RNAs regulates the timing of C. elegans development. The let-7 RNA showed its conservation across species, including H. sapiens. In humans, let-7 was detected at different expression levels in several tissues, including brain, heart, kidney, liver, lung, trachea, colon, small intestine, spleen, stomach, and thymus [82, 83]. |
| | 2001 | The term miRNA is introduced
In addition to lin-4 and let-7, several stRNAs with regulatory functions were discovered using bioinformatics and cDNA cloning. Three papers published in the same issue of Science showed the existence of small RNAs involved in posttranscriptional regulation of target mRNA in vertebrates and invertebrates. These RNAs were named microRNAs (miRNA) to refer to this class of small regulatory RNAs [84–86]. |
| | 2002 | miRNA is associated with cancer
The relevance of miRNAs to cancer was suggested by changes in their expression patterns and recurrent amplification and deletion of miRNA genes in tumors. The first report suggesting a role of miRNAs in cancer described a frequent 13q14 deletion that encoded the miRNA-15a/16-1 cluster reducing its expression in chronic lymphocytic leukemia. Both genes were deleted or downregulated in 68% of analyzed cases. Two years later, the same group found that a significant percentage of miRNAs is located at fragile sites and in genomic regions altered in cancers, including regions of amplification or loss of heterozygosity or breakpoints. They suggested that miRNAs were a new class of genes with a relevant role in human cancer pathogenesis [7, 58]. |
| | 2003 | miRNAs in colorectal cancer
A total of 28 different miRNA sequences were identified in a colonic adenocarcinoma and normal mucosa. Among them, miR-21, miR-143, miR-145, and miR-200c were expressed. In colorectal cancer, two different miRNAs, miR-143 and miR-145 exhibited significantly reduced levels of the mature miRNAs compared to normal mucosa specimens. The maintenance of constant levels of unprocessed hairpin precursors in both normal and tumor tissues suggested that altered transcription is not responsible for reduced miRNA levels. Authors proposed that the reduction is due to posttranscriptional processes such as a reduced Dicer-processing activity in the neoplastic cells or reduced stability of these specific miRNAs [87]. |
| | 2002-2003 | miRBase: the miRNA sequence database
miRBase was established in 2002 as a miRNA registry. The criteria for the identification of miRNAs was published in 2003. The miRBase grew from the miRNA registry resource set up by Griffiths-Jones in 2003 and is the public repository for all published miRNA sequences and annotation data. Its aim is assigning stable and consistent names to newly discovered miRNAs. The first release of miRBase in 2002 contained 218 miRNA loci from five species. Since then, the number of miRNAs discovered has increased exponentially. The miRBase is freely available at http://www.mirbase.org/ [60–62]. |
| | 2004 | miRNAs as molecular biomarkers
let-7 expression is associated with survival of lung cancer patients. This was the first time that miRNAs are suggested as prognostic markers. The article described that let-7 expression was reduced in lung cancers and that lung cancer patients with low let-7 expression levels had a significantly shorter survival after potentially curative resection. Currently, the clinical utility of miRNAs as diagnostic/prognostic biomarkers has been demonstrated in several types of cancer by numerous studies using tumor samples [88]. |
| | 2005 | Function of miRNAs in cancer
The first reports addressing the biological function of miRNAs in cancer were published. These articles described that miR-15 and miR-16, the first two miRNAs associated with cancer, play a role in apoptosis regulation by targeting the antiapoptotic bcl-2 mRNA. They also reported the first miRNA-target interaction with relevance to cancer: human Ras expression is regulated by let-7 in cell culture. In fact, let-7 expression is decreased in lung cancer compared with normal tissue, and it correlates with the increased Ras protein levels detected in lung tumor samples. Since then, hundreds of publications have reported on the role of miRNAs in tumors [89–91]. |
| | 2005 | The expression of miRNAs is regulated by transcription factors
It is described that c-Myc activates the expression of a cluster of six miRNAs on human chromosome 13. In turn, the expression of a target of c-Myc, the transcription factor E2F1, is negatively regulated by two oncogenic miRNAs in this cluster, miR-17-5p and miR-20a [92]. |
| | 2005–2007 | Role of miRNAs as candidate components of oncogene and tumor-suppressor networks
The role of miRNAs as oncogenes (oncomiRs) or tumor suppressors involved in a variety of pathways deregulated in cancer was reported. The polycistronic miRNA cluster miR-17-92, located in a region of DNA that is amplified in human B-cell lymphomas, is reported as a potential human oncogene. Other studies, using different types of tumors,also described the role of miR-143, miR-145, miR-372, miR-373, and miR-155/BIC as oncogenic miRNAs. Conversely, five independent reports describe that the miR-34 family of evolutionarily conserved miRNAs are directly induced by p53 in response to DNA damage and oncogenic stress. miR-34a was identified as a miRNA component of the p53 network, revealing an interplay between proteins and noncoding RNAs in a tumor-suppressor pathway [93–102]. |
| | 2007 | miRNAs “sponges”
The initial term “target mimicry” was coined in plants to define the mechanism of inhibition of miRNA activity discovered studying the phosphate homeostasis in Arabidopsis thaliana. In the same year, there is a report in humans on specific competitive inhibitors from transcripts expressed from strong promoters that contain multiple tandem binding sites to several miRNA seed families; they were named “miRNA sponges” [103, 104]. |
| | 2007–2009 | miRNAs and metastasis
miRNAs are also involved in metastasis; they can promote or inhibit metastasis. The first miRNA described as a metastasis activator was miR-10b, that positively regulates cell migration and invasion in vitro and is capable of initiating tumor invasion and metastasis in vivo. Expression levels of miR-10b in primary breast carcinomas correlate with clinical progression. Its expression is elevated in about 50% of metastatic breast tumors compared with metastasis-free tumors or normal breast tissues. Human miR-373 and miR-520c also stimulate cancer cell migration and invasion in vitro and in vivo. On the contrary, other miRNAs can prevent tumor metastasis. Breast cancer patients with low expression levels of miR-335, miR-126, and miR-206 had a shorter median time to metastatic relapse. Restoration of their expression in breast cancer cell lines decreased the number of metastases in inoculated mice [105–108]. |
| | 2008 | Circulating miRNA biomarkers
miRNAs are detected in blood samples (plasma, platelets, erythrocytes, and nucleated blood cells). This pointed out that endogenous plasma miRNAs are protected in some manner to prevent their degradation. Due to their stability in the circulation, miRNAs began to be considered for their potential use as biomarkers for different pathologies [109–112]. |
| | 2013 | miRNA therapeutics
miR-34a mimic (MRX34) enters Phase 1 clinical study in liver cancer and other solid tumors with liver involvement, as well as hematological malignancies. Regretfully, this study was halted in 2016 due to immune-related serious adverse events [113]. |
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