1. Cancer Biology
Download icon

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
  • Cited 17
  • Views 1,710
  • Annotations
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.

Metrics

  • 1,710
    Page views
  • 312
    Downloads
  • 17
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organism

Further reading

    1. Cancer Biology
    2. Cell Biology

    Fine-tuned repression of Drp1 driven mitochondrial fission primes a 'stem/progenitor-like state' to support neoplastic transformation

    Brian Spurlock et al.
    Short Report

    Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. Also, mitochondrial fission and its opposing process of mitochondrial fusion are emerging as crucial regulators of stemness. Intriguingly, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Using our newly derived carcinogen transformed human cell model we demonstrate that fine-tuned Drp1 repression primes a slow cycling 'stem/progenitor-like state', which is characterized by small networks of fused mitochondria and a gene-expression profile with elevated functional stem/progenitor markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Fine tuning Drp1 protein by reducing its activating phosphorylation sustains the neoplastic stem cell markers. Whereas, fine-tuned reduction of Drp1 protein maintains the characteristic mitochondrial shape and gene-expression of the primed 'stem/progenitor-like state' to accelerate neoplastic transformation, and more complete reduction of Drp1 protein prevents it. Therefore, our data highlights a 'goldilocks'; level of Drp1 repression supporting stem/progenitor state dependent neoplastic transformation.

    1. Cancer Biology
    2. Neuroscience

    Stimulation of hypothalamic oxytocin neurons suppresses colorectal cancer progression in mice

    Susu Pan et al.
    Research Article

    Emerging evidence suggests that the nervous system is involved in tumor development in the periphery, however, the role of central nervous system remains largely unknown. Here, by combining genetic, chemogenetic, pharmacological and electrophysiological approaches, we show that hypothalamic oxytocin (Oxt)-producing neurons modulate colitis-associated cancer (CAC) progression in mice. Depletion or activation of Oxt neurons could augment or suppress CAC progression. Importantly, brain treatment with celastrol, a pentacyclic triterpenoid, excites Oxt neurons and inhibits CAC progression, and this anti-tumor effect was significantly attenuated in Oxt neuron-lesioned mice. Furthermore, brain treatment with celastrol suppresses sympathetic neuronal activity in the celiac-superior mesenteric ganglion (CG-SMG), and activation of β2 adrenergic receptor abolishes the anti-tumor effect of Oxt neuron activation or centrally administered celastrol. Taken together, these findings demonstrate that hypothalamic Oxt neurons regulate CAC progression by modulating the neuronal activity in the CG-SMG. Stimulation of Oxt neurons using chemicals, eg. celastrol, might be a novel strategy for colorectal cancer treatment.

    1. Cancer Biology
    2. Cell Biology

    Identification of abscission checkpoint bodies as structures that regulate ESCRT factors to control abscission timing

    Lauren K Williams et al.
    Research Article Updated

    The abscission checkpoint regulates the ESCRT membrane fission machinery and thereby delays cytokinetic abscission to protect genomic integrity in response to residual mitotic errors. The checkpoint is maintained by Aurora B kinase, which phosphorylates multiple targets, including CHMP4C, a regulatory ESCRT-III subunit necessary for this checkpoint. We now report the discovery that cytoplasmic abscission checkpoint bodies (ACBs) containing phospho-Aurora B and tri-phospho-CHMP4C develop during an active checkpoint. ACBs are derived from mitotic interchromatin granules, transient mitotic structures whose components are housed in splicing-related nuclear speckles during interphase. ACB formation requires CHMP4C, and the ESCRT factor ALIX also contributes. ACB formation is conserved across cell types and under multiple circumstances that activate the checkpoint. Finally, ACBs retain a population of ALIX, and their presence correlates with delayed abscission and delayed recruitment of ALIX to the midbody where it would normally promote abscission. Thus, a cytoplasmic mechanism helps regulate midbody machinery to delay abscission.