NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma

Zhi Jie Xiao, Jing Liu, Si Qi Wang, Yun Zhu, Xu Yuan Gao, Vicky Pui Chi Tin, Jing Qin, Junwen Wang, Maria Pik Wong

Research output: Contribution to journalArticle

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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 is 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.

Original languageEnglish (US)
Article numbere26733
JournaleLife
Volume6
DOIs
StatePublished - Jul 24 2017

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Neoplastic Stem Cells
Tumors
Phenotype
Lung Neoplasms
Neoplasms
Drug therapy
Response Elements
Therapeutics
Oxidative stress
Chemotherapy
Cell Movement
Set theory
Carcinogenesis
Oxidative Stress
Transcription Factors
Up-Regulation
Maintenance
Adenocarcinoma of lung
Calcium
Recurrence

ASJC Scopus subject areas

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

Cite this

Xiao, Z. J., Liu, J., Wang, S. Q., Zhu, Y., Gao, X. Y., Tin, V. P. C., ... Wong, M. P. (2017). NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma. eLife, 6, [e26733]. https://doi.org/10.7554/eLife.26733

NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma. / Xiao, Zhi Jie; Liu, Jing; Wang, Si Qi; Zhu, Yun; Gao, Xu Yuan; Tin, Vicky Pui Chi; Qin, Jing; Wang, Junwen; Wong, Maria Pik.

In: eLife, Vol. 6, e26733, 24.07.2017.

Research output: Contribution to journalArticle

Xiao, ZJ, Liu, J, Wang, SQ, Zhu, Y, Gao, XY, Tin, VPC, Qin, J, Wang, J & Wong, MP 2017, 'NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma', eLife, vol. 6, e26733. https://doi.org/10.7554/eLife.26733
Xiao, Zhi Jie ; Liu, Jing ; Wang, Si Qi ; Zhu, Yun ; Gao, Xu Yuan ; Tin, Vicky Pui Chi ; Qin, Jing ; Wang, Junwen ; Wong, Maria Pik. / NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma. In: eLife. 2017 ; Vol. 6.
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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 is 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.",
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