Precise let-7 expression levels balance organ regeneration against tumor suppression
- University of Texas Southwestern Medical Center, United States
- Boston Children's Hospital and Dana Farber Cancer Institute, United States
- University of Pittsburg, United States
- The First Affiliated Hospital of Sun Yat-Sen University, China
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States
- Harvard Medical School, United States
- Children's Hospital and Dana Farber Cancer Institute, United States
Abstract
The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics.
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Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2012-0143) of the University of Texas Southwestern Medical Center. All surgery was performed under isoflurane anesthesia with appropriate analgesia, and every effort was made to minimize suffering.
Copyright
© 2015, Wu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Precise let-7 expression levels balance organ regeneration against tumor suppression
eLife 4:e09431.
https://doi.org/10.7554/eLife.09431
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