In the journal Cell, researchers reveal that circular RNAs - like their protein counterparts - are also affected by genomic rearrangements in cancer, resulting in abnormal fusions. Moreover, these fusion-circular RNAs are not mere bystanders; they appear to promote tumor growth and progression, underscoring their role in the disease.
Curious about the possibility of circular RNAs contributing to cancer, researchers set out to see if they could detect relevant changes in tumors known to harbor distinct fusion proteins, which result when different chromosomes abnormally join together, melding two separate genes into a new centaur-like gene. These chromosomal translocations are common in various types of leukemia, so the researchers examined two types: acute promyelocytic leukemia, which often carries a translocation between the PML and RARα genes; and acute myeloid leukemia, which can harbor a translocation between the MLL and AF9 genes.
The researchers found abnormal fusion-circular RNAs (f-circRNAs), corresponding to different exons associated with the PML-RARα gene fusion as well as the MLL-AF9 gene fusion. (Normally, multiple circular RNAs can be generated from a single gene, so it is not entirely surprising to find different f-circRNAs emerging from the same fusion gene.)
Remarkably, the authors uncovered f-circRNAs in solid tumors, too -- in samples from Ewing sarcoma, a form of soft tissue cancer, and lung cancer. Moreover, the team identified them using two distinct methods, PCR-based amplification as well as sequencing-based approaches, underscoring f-circRNAs as bona fide biological entities, rather than experimental artifacts.
To determine whether f-circRNAs play a functional role in cancer, the researchers introduced them experimentally into cells, causing the cells to increase their proliferation and tendency to overgrow -- features shared by tumor cells. On the other hand, when the researchers blocked f-circRNA activity, the cells' normal behaviors were restored.
The researchers also conducted experiments using a mouse model of leukemia. They focused on a specific f-circRNA associated with the MLL-AF9 fusion gene, called f-circM9. Although insufficient on its own to trigger leukemia, f-circM9 appears to work together with other cancer-promoting signals (such as the MLL-AF9 fusion protein) to cause disease. Additional studies suggest that f-circM9 may also help tumor cells persist in the face of anti-cancer drugs.
"Indeed, as we look ahead to cataloguing them comprehensively across all cancers and to deeply understanding their mechanisms of action, we will need to propel these new methodologies even further" author said.
Circular RNAs implicated in cancer
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