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. Daley & 2 others Ng Shyh-Chang, Hao Zhu

Research output: Contribution to journalArticle

30 Citations (Scopus)

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

Fingerprint

MicroRNAs
Liver
Tumors
Regeneration
Carcinogenesis
Tissue
Phenotype
Neoplasms
Liver Regeneration
Liver Neoplasms
Phosphatidylinositol 3-Kinases
Oncogenes
Repair
Insulin
Therapeutics

ASJC Scopus subject areas

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

Cite this

Wu, L., Nguyen, L. H., Zhou, K., De Yvanka Soysa, T., Li, L., Miller, J. B., ... Zhu, H. (2015). Precise let-7 expression levels balance organ regeneration against tumor suppression. eLife, 4(OCTOBER2015), [e09431]. https://doi.org/10.7554/eLife.09431

Precise let-7 expression levels balance organ regeneration against tumor suppression. / Wu, Linwei; Nguyen, Liem H.; Zhou, Kejin; De Yvanka Soysa, T.; Li, Lin; Miller, Jason B.; Tian, Jianmin; Locker, Joseph; Zhang, Shuyuan; Shinoda, Gen; Seligson, Marc T.; Zeitels, Lauren R.; Acharya, Asha; Wang, Sam C.; Mendell, Joshua T.; He, Xiaoshun; Nishino, Jinsuke; Morrison, Sean J.; Siegwart, Daniel J.; Daley, George Q.; Shyh-Chang, Ng; Zhu, Hao.

In: eLife, Vol. 4, No. OCTOBER2015, e09431, 07.10.2015.

Research output: Contribution to journalArticle

Wu, L, Nguyen, LH, Zhou, K, De Yvanka Soysa, T, Li, L, Miller, JB, Tian, J, Locker, J, Zhang, S, Shinoda, G, Seligson, MT, Zeitels, LR, Acharya, A, Wang, SC, Mendell, JT, He, X, Nishino, J, Morrison, SJ, Siegwart, DJ, Daley, GQ, Shyh-Chang, N & Zhu, H 2015, 'Precise let-7 expression levels balance organ regeneration against tumor suppression', eLife, vol. 4, no. OCTOBER2015, e09431. https://doi.org/10.7554/eLife.09431
Wu L, Nguyen LH, Zhou K, De Yvanka Soysa T, Li L, Miller JB et al. Precise let-7 expression levels balance organ regeneration against tumor suppression. eLife. 2015 Oct 7;4(OCTOBER2015). e09431. https://doi.org/10.7554/eLife.09431
Wu, Linwei ; Nguyen, Liem H. ; Zhou, Kejin ; De Yvanka Soysa, T. ; Li, Lin ; Miller, Jason B. ; Tian, Jianmin ; Locker, Joseph ; Zhang, Shuyuan ; Shinoda, Gen ; Seligson, Marc T. ; Zeitels, Lauren R. ; Acharya, Asha ; Wang, Sam C. ; Mendell, Joshua T. ; He, Xiaoshun ; Nishino, Jinsuke ; Morrison, Sean J. ; Siegwart, Daniel J. ; Daley, George Q. ; Shyh-Chang, Ng ; Zhu, Hao. / Precise let-7 expression levels balance organ regeneration against tumor suppression. In: eLife. 2015 ; Vol. 4, No. OCTOBER2015.
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