Abstract
Circular RNAs (circRNAs) are a subclass of noncoding RNAs widely expressed in mammalian cells. We report here the tumorigenic capacity of a circRNA derived from angiomotin-like1 (circ-Amotl1). Circ-Amotl1 is highly expressed in patient tumor samples and cancer cell lines. Single-cell inoculations using circ-Amotl1-transfected tumor cells showed a 30-fold increase in proliferative capacity relative to control. Agarose colony-formation assays similarly revealed a 142-fold increase. Tumor-take rate in nude mouse xenografts using 6-day (219 cells) and 3-day (9 cells) colonies were 100%, suggesting tumor-forming potential of every cell. Subcutaneous single-cell injections led to the formation of palpable tumors in 41% of mice, with tumor sizes >1 cm3 in 1 month. We further found that this potent tumorigenicity was triggered through interactions between circ-Amotl1 and c-myc. A putative binding site was identified in silico and tested experimentally. Ectopic expression of circ-Amotl1 increased retention of nuclear c-myc, appearing to promote c-myc stability and upregulate c-myc targets. Expression of circ-Amotl1 also increased the affinity of c-myc binding to a number of promoters. Our study therefore reveals a novel function of circRNAs in tumorigenesis, and this subclass of noncoding RNAs may represent a potential target in cancer therapy.
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Acknowledgements
This work was supported by the Canadian Institutes of Health Research (PJT-149083) to BBY, who is the recipient of a Career Investigator Award (CI 7418) from the Heart and Stroke Foundation of Ontario. WWD is supported by a Postdoctoral Fellowship from the Breast Cancer Foundation of Ontario.
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Yang, Q., Du, W., Wu, N. et al. A circular RNA promotes tumorigenesis by inducing c-myc nuclear translocation. Cell Death Differ 24, 1609–1620 (2017). https://doi.org/10.1038/cdd.2017.86
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DOI: https://doi.org/10.1038/cdd.2017.86
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