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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Authors | Linwei Wu, Liem H Nguyen, Kejin Zhou, T Yvanka de Soysa, Lin Li, Jason B Miller, Jianmin Tian, Joseph Locker, Shuyuan Zhang, Gen Shinoda, Marc T Seligson, Lauren R Zeitels, Asha Acharya, Sam C Wang, Joshua T Mendell, Xiaoshun He, Jinsuke Nishino, Sean J Morrison, Daniel J Siegwart, George Q Daley, Ng Shyh-Chang, Hao Zhu |
Journal | eLife
(Elife)
Vol. 4
Pg. e09431
(Oct 07 2015)
ISSN: 2050-084X [Electronic] England |
PMID | 26445246
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- MicroRNAs
- mirnlet7 microRNA, mouse
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Topics |
- Animals
- Gene Expression Regulation
- Genes, Tumor Suppressor
- Mice
- MicroRNAs
(biosynthesis)
- Neoplasms
(pathology)
- Regeneration
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