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

Linwei Wu, Liem H. Nguyen, Kejin Zhou, T. De Yvanka Soysa, Lin Li, Jason B. Miller, Jianmin Tian, Joseph Locker, Shuyuan Zhang, Gen Shinoda, Marc T. Seligson, Lauren R. Zeitels, Asha Acharya, Sam C. Wang, Joshua T. Mendell, Xiaoshun He, Jinsuke Nishino, Sean J. Morrison, Daniel J. Siegwart, George Q. DaleyNg Shyh-Chang, Hao Zhu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere09431
JournaleLife
Volume4
Issue numberOCTOBER2015
DOIs
StatePublished - Oct 7 2015

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Precise let-7 expression levels balance organ regeneration against tumor suppression'. Together they form a unique fingerprint.

Cite this