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Elife. 2015 Oct 7;4:e09431. doi: 10.7554/eLife.09431.

Precise let-7 expression levels balance organ regeneration against tumor suppression.

Wu L1,2,3, Nguyen LH1,3, Zhou K4, de Soysa TY5,6,7,8, Li L1,3, Miller JB4, Tian J9, Locker J9, Zhang S1,3, Shinoda G5,6,7,8, Seligson MT5,6,7,8, Zeitels LR3,10, Acharya A3,10, Wang SC1,3,11, Mendell JT3,10, He X2, Nishino J12, Morrison SJ12, Siegwart DJ4, Daley GQ5,6,7,8, Shyh-Chang N5,6,7,8,13, Zhu H1,3.

Author information

1
Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States.
2
Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
3
Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
4
Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.
5
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, United States.
6
Harvard Stem Cell Institute, Harvard University, Boston, United States.
7
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
8
The Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.
9
Department of Pathology, University of Pittsburg, Pittsburg, United States.
10
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States.
11
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States.
12
Howard Hughes Medical Institute, Children's Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States.
13
Stem cell and Regenerative Biology, Genome Institute of Singapore, Singapore, Singapore.

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.

KEYWORDS:

MYC; cancer; cell biology; developmental biology; let-7; liver; microRNA; mouse; regeneration; stem cells

PMID:
26445246
PMCID:
PMC4716837
DOI:
10.7554/eLife.09431
[Indexed for MEDLINE]
Free PMC Article

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