Small RNA Suppresses Tumor Cell Growth in a Mouse Model of Liver Cancer
The Bottom Line
A small RNA molecule, known as a microRNA, has been found to inhibit the proliferation of liver cancer cells, selectively trigger liver tumor cell death, and suppress tumor growth in a mouse model of liver cancer. This microRNA may hold potential in the development of a new strategy for treating liver cancer in humans.
The Whole Story
Although treatments for liver cancer have improved substantially, the survival rate overall for patients diagnosed with this disease remains low (only 11 percent survive for 5 years), in part because many patients are diagnosed with advanced disease. Clearly, new approaches to treating liver cancer are urgently needed.
Recently, researchers have discovered that the levels of molecules known as microRNAs are altered in liver and other cancers. These small RNA molecules help regulate gene expression by repressing the translation of target genes. In translation, the information in genes is converted, or "translated," into proteins. In this process, other RNA molecules, called messenger RNAs (mRNAs), are used as blueprints to build specific proteins. There are many types of microRNAs, and a single microRNA can repress the translation of hundreds of different mRNAs.
Although some microRNAs are produced at abnormally high levels in cancer cells, the levels of most microRNAs are reduced in tumors. A research team supported in part by the National Cancer Institute was interested in seeing whether restoring the levels of certain microRNAs in liver cancer cells could stop the proliferation of these cells and block tumor progression. They reasoned that such a strategy might work best for a microRNA that is produced at low levels in tumors but at high levels in normal tissues.
To identify a microRNA that met these criteria in a mouse model of liver cancer, the researchers compared the levels of several microRNAs in normal mouse liver to the levels in mouse liver tumors. They observed the most striking difference for a microRNA known as miR-26a, whose level was dramatically lower in tumors than in normal mouse liver. Furthermore, they found that in seven of eight tested patients with liver cancer, miR-26a levels were lower in tumor tissue than in normal liver tissue.
The researchers next investigated whether experimentally boosting the level of miR-26a in human liver cancer cells grown in the laboratory could block the proliferation of these cells. They found that elevating the level of miR-26a stopped the process of cell division, which leads to proliferation, and substantially reduced the levels of two proteins, cyclin D2 and cyclin E2, that play a critical role in moving cells through the cell division cycle.
Finally, the researchers investigated whether increasing the level of miR-26a in the cancer cells of mice bearing liver tumors could affect disease progression. To do this, they modified a virus that is known to target liver cells specifically. They genetically engineered the virus so infected cells would produce miR-26a and a protein called fluorescent green protein simultaneously. This approach allowed the researchers to estimate the percentage of liver cells (normal and cancerous) that became infected and, therefore, able to produce high levels of miR-26a. (The infected cells give off green fluorescent light.) The researchers determined that over 90 percent of liver cells became infected by this method.
To treat tumor-bearing mice, the researchers injected the modified virus into the bloodstream of animals that had multiple small-to-medium sized tumors in their livers. Several weeks later, eight of 10 treated mice had only small tumors or no tumors at all in their livers. In contrast, six of eight mice that received a control virus developed severe disease in which the majority of normal liver tissue was replaced by tumor tissue. Additional experiments showed that miR-26a achieved its effects by suppressing cancer cell proliferation and activating programmed cell death in liver tumor cells but not in normal liver cells.
Overall, the results of this study suggest that restoring miR-26a to normal or higher levels in liver cancer cells has the potential to provide an effective new approach for treating liver cancer. The researchers note that it is likely that many equally or more effective microRNAs with potential as cancer therapies remain to be identified.
More summaries of selected scientific advances from NCI-supported research are available at http://www.cancer.gov/aboutnci/servingpeople/advances.