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

  1. Linwei Wu
  2. Liem H Nguyen
  3. Kejin Zhou
  4. T Yvanka de Soysa
  5. Lin Li
  6. Jason B Miller
  7. Jianmin Tian
  8. Joseph Locker
  9. Shuyuan Zhang
  10. Gen Shinoda
  11. Marc T Seligson
  12. Lauren R Zeitels
  13. Asha Acharya
  14. Sam C Wang
  15. Joshua T Mendell
  16. Xiaoshun He
  17. Jinsuke Nishino
  18. Sean J Morrison
  19. Daniel J Siegwart
  20. George Q Daley
  21. Ng Shyh-Chang
  22. Hao Zhu  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. Boston Children's Hospital and Dana Farber Cancer Institute, United States
  3. University of Pittsburg, United States
  4. The First Affiliated Hospital of Sun Yat-Sen University, China
  5. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States
  6. Harvard Medical School, United States
  7. Children's Hospital and Dana Farber Cancer Institute, United States

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.

Article and author information

Author details

  1. Linwei Wu

    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  2. Liem H Nguyen

    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  3. Kejin Zhou

    Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  4. T Yvanka de Soysa

    Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  5. Lin Li

    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  6. Jason B Miller

    Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  7. Jianmin Tian

    Department of Pathology, University of Pittsburg, Pittsburg, United States
    Competing interests
    No competing interests declared.
  8. Joseph Locker

    Department of Pathology, University of Pittsburg, Pittsburg, United States
    Competing interests
    No competing interests declared.
  9. Shuyuan Zhang

    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  10. Gen Shinoda

    Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  11. Marc T Seligson

    Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  12. Lauren R Zeitels

    Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  13. Asha Acharya

    Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  14. Sam C Wang

    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  15. Joshua T Mendell

    Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  16. Xiaoshun He

    Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
    Competing interests
    No competing interests declared.
  17. Jinsuke Nishino

    Children's Medical Center Research Institute at UT Southwestern, Department of Pediatrics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  18. Sean J Morrison

    Children's Medical Center Research Institute at UT Southwestern, Department of Pediatrics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    Sean J Morrison, Senior editor, eLife.
  19. Daniel J Siegwart

    Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  20. George Q Daley

    Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  21. Ng Shyh-Chang

    Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Children's Hospital and Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  22. Hao Zhu

    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Hao.Zhu@utsouthwestern.edu
    Competing interests
    No competing interests declared.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2012-0143) of the University of Texas Southwestern Medical Center. All surgery was performed under isoflurane anesthesia with appropriate analgesia, and every effort was made to minimize suffering.

Copyright

© 2015, Wu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Linwei Wu
  2. Liem H Nguyen
  3. Kejin Zhou
  4. T Yvanka de Soysa
  5. Lin Li
  6. Jason B Miller
  7. Jianmin Tian
  8. Joseph Locker
  9. Shuyuan Zhang
  10. Gen Shinoda
  11. Marc T Seligson
  12. Lauren R Zeitels
  13. Asha Acharya
  14. Sam C Wang
  15. Joshua T Mendell
  16. Xiaoshun He
  17. Jinsuke Nishino
  18. Sean J Morrison
  19. Daniel J Siegwart
  20. George Q Daley
  21. Ng Shyh-Chang
  22. Hao Zhu
(2015)
Precise let-7 expression levels balance organ regeneration against tumor suppression
eLife 4:e09431.
https://doi.org/10.7554/eLife.09431

Share this article

https://doi.org/10.7554/eLife.09431

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