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Research Team Publishes Data Showing Gene Regulation by Secreted microRNAs

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By Doug Macron

A team of Chinese researchers this week published data demonstrating that cells can selectively package microRNAs in microvesicles, which are actively secreted and trigger target gene inhibition in recipient cells.

The findings, which appeared in Molecular Cell, not only show that miRNAs are "a novel class of signaling molecules that play an important role in mediating cell-to-cell and organ-to-organ communication," but also demonstrate that the small, non-coding RNAs are part of "a highly regulated complex network under various physiological and pathophysiological conditions," Nanjing University researcher and senior author of the study Chen-Yu Zhang told Gene Silencing News in an e-mail.

According to Zhang, the new paper built off of an earlier study published in Cell Research in which he and his colleagues found that miRNAs are stably expressed in animal serum and plasma, and that their expression patterns were associated with diseases including lung cancer, colorectal cancer, and diabetes.

"By characterizing serum miRNA expression profiles under normal physiological conditions and in various disease states, we found that serum miRNAs are derived not only from circulating blood cells but also from other tissues directly affected by disease," the team wrote of their Cell Research work.

"Interestingly, unlike miRNAs extracted from tissues or cells, miRNA extracted from sera are resistant to RNase A digestion, suggesting that serum miRNAs might be modified differently from tissue or cellular miRNAs"

Still, "the mechanisms that regulate miRNA release and the potential biological functions of serum miRNAs are completely unknown," the researchers noted in Molecular Cell.

In light of research that found miRNAs in a microvesicles derived from glioblastoma cells, and a study that showed that transferred exosomal mRNA can be translated after entering a new cell, Zhang and colleagues hypothesized that microvesicles could possibly serve as carriers for circulating miRNAs.

"We thought there were two possibilities" to explain the presence of stable miRNAs in serum and plasma, he said in his e-mail. The first was that the miRNAs were modified before leaving the cell, and the second was that they were associated with a vesicle or binding protein.

Because free miRNAs cannot pass through the cellular membrane, "we started to check [for] possible carriers and binding proteins," and successfully identified miRNAs within microvesicles, Zhang added.

Previously, there was no "direct evidence to show that exogenous miRNAs delivered by [microvesicles] regulate the expression of target genes and cellular functions in recipient cells," he and his team wrote in this week's paper. And because microvesicles contain proteins and various nucleotides, and effects they have on recipient cells may not be due to the miRNAs.

But in a series of experiments detailed in Molecular Cell, Zhang and his team demonstrated that in human blood cells and cultured THP-1 cells, a specific miRNA, miR-150, was "selectively packaged into microvesicles and actively secreted."

Further, they showed that THP-1-derived microvesicles entered and delivered miR-150 into human HMEC-1 cells, where they decreased expression of their target, the transcription factor c-Myb, and "enhanced cell migration in HMEC-1 cells," according to the paper.

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"Our results demonstrated that miRNAs in [microvesicles] can also alter the gene in the target cells … [which] is direct evidence that a secreted miRNA specifically regulates a biological function of the recipient cells. Our results can therefore be taken to show that secreted miRNAs in circulation have a great potential to become a class of signaling molecules that mediate intercellular/interorgan communication," they added.

While some researchers have theorized that miRNAs are released into circulation from broken cells, Zhang and colleagues noted that if this is the case, there would be no selective packaging of the miRNAs into the microvesicles "and the ratio of released miRNAs would be similar to that in the cells.

"However, our results have demonstrated that cells selectively package miRNAs … in circulating blood cells and in cultured THP-1 cells under various stimuli," including exposure to inflammatory factors that alter macrophage function, they wrote.

Microvesicles isolated from the plasma of patients with atherosclerosis contained higher levels of miR-150 compared with microvesicles from healthy individuals, and these down-regulated c-Myb while enhancing HMEC-1 cell migration, according to the paper.

Since the migration of endothelial cells lining blood vessels is a "major component of atherosclerosis, it appears likely that elevated miR-150 levels in [microvesicles] could mediate crosstalk between circulating monocytes/macrophages and vascular endothelial cells under various pathophysiological conditions," Zhang's team wrote.

On the in vivo side, Zhang's team reported that intravenous injection of THP-1 microvesicles significantly boosted the levels of miR-150 in mouse blood vessels. While this is an "interesting finding," and suggests a "cross-species delivery" of miRNAs via microvesicles, the mechanism underlying this process remains "completely unknown," the team noted.

"It is not clear whether the cross-species delivery of miRNAs is specific and mediated by protein-protein interactions or non-specific and mediated by lipid-carbohydrate interactions," they stated.

With these data in hand, Zhang told Gene Silencing News that his research team now aims to identify and characterize the biological functions of secreted miRNAs in "various physiological and pathophysiological conditions," while trying to better their understanding of the mechanism that regulates miRNA secretion.

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