What is a microRNA?
According to the current convention, a miRNA is defined as a ssRNA of ~22 nucleotides in length, which is generated by the RNase-III-type enzyme Dicer from an endogenous transcript that contains a local hairpin structure.
MicroRNAs and cancer
Three important observations early in the history of miRNAs suggested a potential role in human cancer. Firstly, the earliest miRNAs discovered in the roundworm C. elegans and the fruit fly Drosophila were shown to control cell proliferation and apoptosis. Their deregulation may therefore contribute to proliferative diseases such as cancer. Secondly, when human miRNAs were discovered, it was noticed that many miRNA genes were located at fragile sites in the genome or regions that are commonly amplified or deleted in human cancer. Thirdly, malignant tumors and tumor cell lines were found to have widespread deregulated miRNA expression compared to normal tissues. The question remained whether the altered miRNA expression observed in cancer is a cause or consequence of malignant transformation.
MicroRNAs as causal cancer genes at genomic breakpoints :-
Five years ago, the first direct evidence for an involvement of miRNAs in cancer was reported. Calin et al. studied a well-known deletion on chromosome13, which is the most frequent chromosomal abnormality in chronic lymphocytic leukemia (CLL). This deletion had long been suspected to contribute to leukemogenesis. However, extensive studies had failed to identify a causal gene. Calin et alfound that two miRNA genes, mir-15 and mir-16, were located within this 30-kb deletion. They subsequently analyzed the expression of miR-15 and miR-16 in blood samples from patients with CLL. Both miRNAs were absent or down-regulated in the majority (68%) of cases when compared to normal tissue or lymphocytes. This finding suggested that these two miRNAs were causally involved in the pathogenesis of chronic lymphocytic leukemia. In 2005, three reports provided the first mechanistic insight into how miRNAs might contribute to carcinogenesis. Two independent studies described the relationship between a miRNA cluster, mir-17-92, and the Myc oncogenic pathway. A third report demonstrated an interaction between let-7 miRNA and the RAS proto-oncogene.
MicroRNAs with oncogenic Potential:-
A cluster of six miRNAs, the mir-17-92 cluster, was found to be located within a region on chromosome 13 that is commonly amplified in human B-cell lymphomas. It has been demonstrated that the miRNAs from the mir-17-92 cluster were over expressed in lymphoma cell lines carrying this amplification, and expression levels correlated with gene copy number of the mir-17-92 locus. Further, the miR-17-92 primary transcript was found to be over expressed in tumor samples from lymphoma patients. mir-17-92 was the first potential non-coding oncogene, referred to as oncomir-1.The cellular function of miR-17-92 was not. Nevertheless, the pathology of the tumors indicated lower rates of apoptosis as compared to tumors with Myc over expression alone. Three recent studies contributed towards our understanding of the oncogenic potential of miR-17-92. Two reports demonstrated an anti-apoptotic effect of miR-17-92 through various pathways that promote cell proliferation and growth. A third study identified mir-17-92 as a mediator of angiogenesis in tumors induced by the oncogene c-Myc. The transcription factor Myc induces expression of E2F1 growth factor. The mir-17-92 cluster which is also induced by c-Myc does, in contrast, inhibit E2F1 expression. The example of the mir-17-92 cluster highlights that a distinction between oncogenic and tumor suppressor miRNAs is likely to be an oversimplification. The same miRNAs may have oncogenic or tumor suppressor activity depending on the context and the cell type they are expressed in. A single miRNA may regulate various unrelated target genes and thereby control opposing activities such as cellular proliferation and apoptosis. The ultimate function of a miRNA may depend on the tissue type they are expressed in and what target genes are present.
MicroRNAs with tumor suppressor potential :-
The let-7 family of miRNAs was the first group of miRNAs shown to regulate expression of a proto-oncogene, the RAS protein. RAS proteins are membrane-associated signaling proteins that regulate cell growth and differentiation. A miRNA that controls expression of these potentially oncogenic proteins would be predicted to possess tumor suppressor activity. Mutations in the RAS oncogene are present in approximately 15–30% of all human cancers, and over expression of the RAS oncogene is common in lung cancer.Over expression of RAS protein in lung cancer tissue correlated with reduced expression of let-7 miRNA.
MicroRNAs in the p53 tumor suppressor network :-
Transcriptional networks are often deregulated in cancer cells and may lead to altered transcription of miRNA genes. Two recent studies identified a miRNA, miR-34, to be regulated by the p53 transcription factor. The p53 protein, also called “the guardian of the genome”, regulates the cellular response to stress and cancer-initiating events such as DNA damage. It has been found that a miRNA, miR-34, is directly activated by the transcription factor p53 after DNA damage. Expression of miR-34 induces cell cycle arrest and thereby acts together with other effectors of the p53 tumor suppressor network to inhibit inappropriate cell proliferation. These data indicate that altered expression of miRNAs is not simply a secondary event that reflects the less differentiated state of cancer cells. In contrast, at least in some cases, miRNA expression is specifically driven by tumor suppressors and oncogenes.
MicroRNAs with a role in tumor invasion and metastasis :-
Transcriptional networks may drive miRNA expression in cancers. Recent work suggested a model by which a pleiotropic transcription factor, Twist, induces expression of a specific miRNA, which suppresses its direct target and in turn activates a pro-metastatic gene, leading to tumor cell invasion and metastasis. The expression of miR-10b induced by the transcription factor Twist promoted cell migration and invasion in mouse and human breast cancer cells. Furthermore, the expression level of miR-10b in primary human breast carcinomas correlated with clinical progression. These findings, if confirmed, suggest that specific miRNAs may have a role beyond the tumor-initiating event and directly participate in tumor progression and metastasis.
MicroRNA profiling—implications for cancer diagnosis :-
Micro-RNA expression profiles clearly differentiated human cancers according to their developmental origin Cancers of epithelial and hematopoietic origin had distinct miRNA profiles. A subgroup of gastrointestinal tumors, which arise from endoderm, was distinguished by miRNA expression patterns. Furthermore, tumors within a single cell lineage such as acute lymphoblastic leukemia were further differentiated according to their underlying genetic abnormality into BCR/ABL-positive tumors, T-cell tumors, and those with MLL gene rearrangement. Gene expression profiling based on 16,000 messenger RNAs did not accurately classify the tumors. This has potential important clinical implications. If miRNAs prove useful for clinical diagnosis, their key advantage might be their high stability. In contrast to most messenger RNAs, they are long-lived in vivo and very stable in vitro, which might allow analysis of paraffin embedded samples for routine diagnostic applications.
Regulation of miRNAs in cancer—who regulates the regulators?
In few cases, the underlying cause of miRNA deregulation in cancer is clear.The over-expression of miR-17-92 correlates with amplification of its gene locus. Similarly, decreased expression of miR-15 and miR-16 is associated with a corresponding chromosomal deletion. Transcriptional or epigenetic regulation of miRNAs has been recently reported .The transcription of a miRNA gene, mir-124a, was shown to be inactivated by hyper-methylation of its promoter in various human tumors. This process of epigenetic silencing is a well-known mechanism to inactivate protein-coding genes in cancer cells and may similarly apply to miRNAs. The miRNA gene mir-127 is usually expressed in normal cells but not in cancer cells. Disrupted repression of Hmga2 by let-7 promoted oncogenic transformation and growth in mammalian cells. There is evidence that miRNAs are regulated indirectly through control of their processing enzymes. It is proved that a down regulation of miRNAs in human cancer was not associated with reduced levels of the primary miRNA transcripts.