Naturally occurring strands of a special type of RNA may silence cancer-suppressing genes, according to a report by Hopkins scientists published this month in Nature. Once turned off, the genes - called tumor suppressor genes (TSGs) - no longer keep cell growth in check, often resulting in the development of cancerous tumors.
Scientists have long known that some people are more likely than others to develop cancer based on their individual genetic make-ups. But that fact does not explain why only a few cells take the proverbial wrong turn, since every cell in the body contains the same DNA sequence.
The reason why only a handful of cells become cancerous has remained somewhat of a mystery, but some intriguing clues have surfaced, thanks in large part to the study of how non-genetic influences shape gene expression, a field called epigenetics.
Epigenetic modification allows cells to maintain different characteristics over the course of several replications and divisions without actually changing any DNA sequences. This is especially important in development. Stem cells, for example, branch out into many different cell types despite the fact that they all possess the same unchanging genome.
By turning certain genes on or off (as the case may be) at different times, epigenetic changes determine which progenitors become liver cells and which become skin cells.
Nonetheless, not all epigenetic influence is good: switching genes on and off can lead to a host of diseases, including cancer, which is where the Hopkins researchers directed their attention.
There is a long and growing list of epigenetic processes, but the team, lead by Hengmi Cui of the School of Medicine, focused on gene silencing in particular. Even more specifically, they wanted to test the hypothesis that antisense RNA - a special type of nucleic acid, the group of macromolecules that function as a cell's genetic library - may be the culprit in the turning-off of certain TSGs in cancerous cells.
Antisense RNA are non-coding; that is, the information they carry never gets used in the stringing-together of amino acids to make protein (the final product of every gene).
In fact, antisense RNA actually inhibits gene translation. Most antisense RNA is complementary to other, functional strands of RNA called messenger RNA (mRNA). By binding to its complementary mRNA, the antisense variety can physically prevent any translation from taking place.
In the present case, blocking tumor-suppressing genes from making their protein products can lead to tumor growth.
The Hopkins team chose to study the role of a single antisense RNA in silencing a single TSG, dubbed p15, which had previously been linked to leukemia. They analyzed a strain of leukemia cells and found that the majority had notably increased levels of antisense p15 in addition to notably decreased levels of normal p15.
Other tests uncovered a fairly reliable, inverse relationship between antisense and normal p15 - solid evidence that antisense p15 was somehow turning off its normal p15 counterpart.
The researchers then inserted the gene for antisense p15 into a cell containing a normal p15 gene. Not surprisingly, much less normal p15 was produced in comparison to cells without the antisense gene. Chemically neutralizing the antisense RNA returned normal p15 levels to their original levels.
The team went even further: inspection of the DNA that made up the normal p15 gene showed that it was abnormally compacted and tightened into what geneticists call heterochromatin, a telltale sign of gene silencing.
Nonetheless, the precise biochemical processes by which antisense RNA shuts off genes remain a mystery. Still, the Hopkins team said, the presence of high levels of antisense RNA for tumor-suppressing genes may be used in the future as a marker of cancer risk.
