Wu, LinweiNguyen, Liem HZhou, Kejinde Soysa, T YvankaLi, LinMiller, Jason BTian, JianminLocker, JosephZhang, ShuyuanShinoda, GenSeligson, Marc TZeitels, Lauren RAcharya, AshaWang, Sam CMendell, Joshua THe, XiaoshunNishino, JinsukeMorrison, Sean JSiegwart, Daniel JDaley, GeorgeShyh-Chang, NgZhu, Hao2016-02-012015Wu, L., L. H. Nguyen, K. Zhou, T. Y. de Soysa, L. Li, J. B. Miller, J. Tian, et al. 2015. “Precise let-7 expression levels balance organ regeneration against tumor suppression.” eLife 4 (1): e09431. doi:10.7554/eLife.09431. http://dx.doi.org/10.7554/eLife.09431.2050-084Xhttp://nrs.harvard.edu/urn-3:HUL.InstRepos:24983891The 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. DOI: http://dx.doi.org/10.7554/eLife.09431.001en-USlet-7regenerationcancerlivermicroRNAMYCMouseJournal Article2016-02-0110.7554/eLife.09431