1. Cancer Biology
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NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma

  1. Zhi-Jie XIAO
  2. Jing Liu
  3. Si-Qi Wang
  4. Yun Zhu
  5. Xu-Yuan Gao
  6. Vicky Pui-Chi Tin
  7. Jing Qin
  8. Jun-Wen Wang
  9. Maria Pik Wong  Is a corresponding author
  1. The University of Hong Kong, Hong Kong
  2. The Chinese University of Hong Kong, Hong Kong
  3. MayoClinic, United States
Research Article
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Cite this article as: eLife 2017;6:e26733 doi: 10.7554/eLife.26733

Abstract

Tumor initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals. Mechanistic investigations identified NFATc2 response elements in the 3' enhancer region of SOX2, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5' enhancer. Through this axis, oxidative stress induced by cancer drug treatment are attenuated, leading to increased resistance in a mutation-independent manner. Targeting this axis provides a novel approach for the long term treatment of lung cancer through TIC elimination.

Article and author information

Author details

  1. Zhi-Jie XIAO

    Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  2. Jing Liu

    Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  3. Si-Qi Wang

    Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  4. Yun Zhu

    Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  5. Xu-Yuan Gao

    Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  6. Vicky Pui-Chi Tin

    Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  7. Jing Qin

    School of life sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  8. Jun-Wen Wang

    Department of Health Sciences Research, MayoClinic, Scottsdale, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Maria Pik Wong

    Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong
    For correspondence
    mwpik@hku.hk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4028-926X

Funding

Research Grants Council, University Grants Committee (HKU 17123514 M)

  • Zhi-Jie XIAO
  • Jing Liu
  • Si-Qi Wang
  • Yun Zhu
  • Xu-Yuan Gao
  • Vicky Pui-Chi Tin
  • Maria Pik Wong

University of Hong Kong

  • Zhi-Jie XIAO
  • Jing Liu
  • Si-Qi Wang
  • Yun Zhu
  • Xu-Yuan Gao
  • Vicky Pui-Chi Tin
  • Maria Pik Wong

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed after approval by the Animal Ethics Committee, the University of Hong Kong according to issued guidelines. (CULATR No.4020-16)

Reviewing Editor

  1. Joaquín M Espinosa, University of Colorado School of Medicine, United States

Publication history

  1. Received: March 13, 2017
  2. Accepted: July 22, 2017
  3. Accepted Manuscript published: July 24, 2017 (version 1)
  4. Version of Record published: August 24, 2017 (version 2)

Copyright

© 2017, XIAO 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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