Abstract PR07: Precise let-7 expression levels balance organ regeneration against tumor suppression

Abstract

Abstract 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.