How MicroRNAs Drive Cancer—with Both Strands

Researchers have long thought that only one strand of a double-stranded microRNA is used to silence genes. Though recent evidence has challenged that dogma, it’s still unclear what the other strand does and how the two may be involved in cancer.

New research from Thomas Jefferson University has revealed that both strands of some microRNA coordinate to act on the same cancer pathways, across multiple cancers, to drive aggressiveness and growth. The work was published today in Nature Communications.

“This coordination of activity is really surprising," says senior author Christine M. Eischen. “We know that the strands don’t hit the same target sequences. But despite that fact, we see that they are working together.”

Researchers have not paid much attention to both sides of the microRNA, in part because reagents created to probe microRNAs were aimed at only one strand. “As a field, we weren’t looking at the whole picture,” Eischen says.

To remedy this, first author Ramkrishna Mitra used a computational approach that allowed him to search for both strands of the microRNA. “Our data showed that one strand of many of the pairs were not degraded as previously thought,” he says. “We saw large numbers of both pairs in many cancers.”

The team then developed a new computational biology approach, in part, through the analysis of the genes essential for cancer cell survival and growth across 290 cancer cell lines to identify the pathways both microRNA pairs impacted across multiple cancer types. The researchers also determined which microRNA pairs had a bigger impact on driving or suppressing cancer growth together than either strand alone.

They found two pairs, miR-30a and miR-145, that fit the bill. “Each pair has different target genes, but the targets hit the same cancer pathways,” Eischen explains. “These microRNAs help keep cancers in check—as seen both in patient data and in tumor cell lines. As a result, many cancers, such as kidney, lung, breast, become more aggressive when they lose these microRNAs, and this impacts patient survival.”

To validate the findings of their computational work, the researchers replicated what they found using an experimental approach. They forced expression of miR-145 and miR-30a in lung cancer cell lines, which reduced the cancer’s aggressive traits—specifically its growth and migration.