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

Elife. 2015 Oct 7;4:e09431. doi: 10.7554/eLife.09431.

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.

Keywords: MYC; cancer; cell biology; developmental biology; let-7; liver; microRNA; mouse; regeneration; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation*
  • Genes, Tumor Suppressor*
  • Mice
  • MicroRNAs / biosynthesis*
  • Neoplasms / pathology*
  • Regeneration*

Substances

  • MicroRNAs
  • mirnlet7 microRNA, mouse