The in vivo roles for even the most intensely studied microRNAs remain poorly defined. We interrogated the physiological functions of let-7, a large and ancient microRNA family that is well-known for regulating developmental timing, metabolism, and cancer. Analysis of mouse models revealed that let-7 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, achieved by genetic induction or by lipid nanoparticle delivery, abrogated the development of aggressive MYC-driven liver cancer and provided a robust survival benefit by antagonizing let-7 sensitive oncogenes (Cdc25a, Cdc34, E2f2, E2f5, and Map4k4). However, the same level of overexpression blocked liver regeneration, while deletion of two let-7 family members significantly enhanced it, demonstrating that distinct levels of this microRNA can mediate desirable phenotypes. The observed 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 family in development, and have important implications for let-7 based therapeutics.
Citation Format: Liem Hieu Nguyen, Linwei Wu, Hao Zhu. Precise let-7 expression levels balance organ regeneration against tumor suppression. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr PR07.