Precise Let-7 Expression Levels Balance Organ Regeneration against Tumor Suppression


Authors: Zhou K, Nguyen LH, Miller JB, Yan Y, Kos P, Xiong H, Li L, Hao J, Minnig JT, Zhu H, Siegwart DJ

Journal: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.1520756113

Publication - Abstract

January 01, 2016

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-7in 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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