miRNA and diseaseFebruary 21, 2012
miRNAs are post-transcriptional regulators of gene expression that bind to complementary sequences on target messenger RNA transcripts (mRNAs) present inside the cell, usually resulting in translational repression or target degradation and gene silencing.
Transgenic mice that over-express or lack specific miRNAs have provided insight into the role of small RNAs in various malignancies. Several miRNAs have been found to have links with some types of cancer. MicroRNA-21 is one of the first microRNAs that was identified as an onco-miR. A study of genetically modified mice altered to produce oncogene c-Myc implicated in several cancers — shows that miRNA has an effect on the development of cancer. Mice that were engineered to produce an excess of miRNAs found in lymphoma cells developed the disease within 50 days and died two weeks later. In contrast, mice without the surplus miRNA lived over 100 days. Leukemia can be caused by the insertion of a viral genome next to the 17-92 array of microRNAs leading to increased expression of this microRNA.
A mutation of miR-96 causes hereditary progressive hearing loss. A mutation in the seed region of miR-184 causes hereditary keratoconus with anterior polar cataract. Deletion of the miR-17~92 cluster causes skeletal and growth defects.
Another study found that two types of miRNA inhibit expression of the E2F1 protein, which regulates cell proliferation. miRNA appears to bind to messenger RNA before it can be translated to proteins that switch genes on and off.
miRNA “signatures” may enable classification of cancer. By measuring expression levels of some 217 genes encoding miRNA, scientists were able to distinguish several types of cancer. This will allow doctors to determine the original tissue type which spawned a cancer and to be able to target a treatment course based on the original tissue type. miRNA profiling has already been able to determine whether patients with chronic lymphocytic leukemia had slow growing or aggressive forms of the cancer.
A novel miRNA-based screening assay for the detection of early-stage colorectal cancer has been developed and is currently in clinical trials. Early results showed that blood plasma samples collected from patients with early, resectable (Stage II) colorectal cancer could be distinguished from those of sex-and age-matched healthy volunteers. Sufficient selectivity and specificity could be achieved using small (less than 1 mL) samples of blood. The test has potential to be a cost-effective, non-invasive way to identify at-risk patients who should undergo colonoscopy.
Another role for miRNA in cancers is to use their expression level as a prognostic, for example one study on NSCLC samples found that low miR-324a levels could serve as a prognostic indicator of poor survival, another found that either high miR-185 or low miR-133b levels correlated with metastasis and poor survival in colorectal cancer.
The global role of miRNA function in the heart has been addressed by conditionally inhibiting miRNA maturation in the murine heart, and has revealed that miRNAs play an essential role during its development. miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in cardiomyopathies. Furthermore, studies on specific miRNAs in animal models have identified distinct roles for miRNAs both during heart development and under pathological conditions, including the regulation of key factors important for cardiogenesis, the hypertrophic growth response, and cardiac conductance.
Extra-cellular RNAs were first identified in the blood just three years ago. In September, a Chinese research team reported that fragments of genetic material known as microRNAs (miRNA) are making their way from vegetables into the human bloodstream. Even more surprising, these bits of plant genome may affect health suggesting that some biomolecules can remain active even after digestion.
Biochemist Chen-Yu Zhang of Nanjing University suspected that foreign miRNA might also be present there. “I had the crazy idea to check for nonhuman molecules,” Zhang says. He and his team tested hundreds of volunteers and found about 50 different kinds of plant miRNAs in their blood samples. The scientists noticed that one such molecule, called MIR168a—which is abundant in rice and plays a role in plant development—paired up with a piece of human RNA that helps remove “bad” LDL cholesterol from the bloodstream. Follow-up tests in human cell cultures confirmed that MIR168a interferes with production of a cholesterol-clearing protein. And an experiment with mice showed that LDL cholesterol stuck around longer in the blood of the animals who had eaten rice than in those who had not.