Like a second lock on a door, a team of microRNAs (miRNAs) provides a backup layer of protection against cancer, Marzi et al. show.
The levels of many miRNAs plummet in cancer cells. Studies suggest that this decline promotes cell division and makes tumors more aggressive, but researchers haven’t worked out how. Marzi et al. suspected that the loss of miRNAs might be harmful because they normally combine forces with regulatory gene pathways to keep cell proliferation in check.
They tested the idea by engineering terminally differentiated muscle cells to express the oncogene E1A, which spurs the cells to “unspecialize” and reenter the cell cycle. E1A counteracts the tumor suppressor gene Retinoblastoma (Rb), and the team found that many of the genes that E1A induces foster cell division and are usually suppressed by Rb.
An independent layer of tumor suppression emerged when the team measured E1A’s effects on more than 300 miRNAs. They identified 56 miRNAs whose levels changed upon E1A expression; E1A suppressed miRNAs that are normally produced during differentiation and unleashed miRNAs that induce proliferation. The researchers found that most of the miRNAs involved in differentiation were expressed independently of Rb and were instead regulated by the transcription factors Myc and MyoD. Seven of these miRNAs curbed division of immature muscle cells and stimulated their differentiation. The researchers conclude that these miRNAs constitute a distinct regulatory mechanism that curbs cancer development.