reviews Micro RNA and its Tremendous Role in Cancer Olesya Levsh, ‘13
Colorectal cancer is the second leading cause of death from cancer in the Western world. Gastric cancer is the second leading cause of death for men, and the third for women. The fifth leading cancer-related cause of death is cancer of the liver, while pancreatic cancer has been deemed the fourth . Among these numbers, hope dawns in the form of a prominent figure emerging in the field of oncology, and, though it is tiny, it is revolutionizing both our understanding of carcinogenesis and our ability to diagnose various cancers in phenomenal ways. Thanks to micro RNAs (miRNAs), scientists have been able to pinpoint patterns of expression so precisely that they have stumbled upon what may essentially be fingerprints for various types of cancers, complete with developmental history of the tumor. Shedding a new light on carcinogenic pathways gone awry, miRNA has helped spur progress in treatment as well as diagnosis. A miRNA is a short (21 to 25 nucleotides), non-coding, negative regulator of gene expression. These molecules have the power to either destroy or inhibit the translation of messenger RNA, or mRNA, into protein. The mechanism by which this occurs involves one strand of a double-stranded miRNA entering an enzyme called RNA-induced silencing complex, or RISC, where it base pairs with a strand of mRNA and causes either its destruction or its inhibition. The difference in action is determined by the degree of mismatch between the base pairs of the two strands, and because this is the case, it is possible for each miRNA to target multiple genes for regulation . These tiny, non-coding genes, discovered only two decades ago, are estimated to regulate over a third of all coding genes . The link between miRNA and gene expression is the very factor that implicates miRNA in its involvement with cancer. Cancer, as most know it, is a virulent mass of cells that does not cease replicating – but at the cellular level, it is much more complicated. For cells to become cancerous, they must ignore signals that tell them to undergo apoptosis (programmed cell death), checkpoints in the mitotic cycle, and a multitude of other feedback mechanisms. This provides cancerous cells with what are known to be their hallmark characteristics: unrestrained replicative potential and immortality. As long as cancerous cells continue to replicate and exhaust nutrients, such as oxygen, they will not die. And, unlike most cells, cancerous cells will never reach a phase of cellular senescence, or inability to undergo mitosis. They will trudge onward, dividing stubbornly regardless of what goes wrong – even if it is something as serious as improper DNA replication. What could be the reason that these cells are so out of control? There is no simple answer. Responsible for this uncontrolled behavior is an amalgamation of several things, among which is gene expression. Research has linked miRNAs to gene amplification, deletion, and mutation – all of which contribute to the development of cancer. And because a single miRNA has the potential to affect many mRNAs, small changes in the
Figure 1. The cellular mechanism for production of miRNA.
expression of miRNAs can cause large changes in a cell’s protein diversity. For example, miR-100 is a potential target of the HOXA1 (HomeoboxA1) and IGF1R (insulin-like growth factor 1 receptor) genes, and has been shown to target the Plk1 gene, involved in regulation of mitosis . The more researchers are delving into the mystery behind these miRNAs, the more they find that the proposed scenario makes sense. Typically, as cancerous cells become more harmful, they also become less differentiated. Experimentally, it has been shown that levels of miRNA are elevated when cells differentiate – in fact, cellular levels of miRNA are an accurate representation of differentiation, and within a cancerous cell, miRNA levels are lower than those within a healthy cell. All of these findings point to an inverse relationship between miRNA expression and cell differentiation . Since it is important to determine the origin of a tumor before treating
The Stony Brook Young Investigators Review, Fall 2011