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.
Keywords:
ALDH1A1; NFATc2; SOX2; cancer biology; human; tumor-initiating cells.
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / genetics*
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Adenocarcinoma / mortality
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Adenocarcinoma / pathology
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Adenocarcinoma of Lung
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Aged
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Aldehyde Dehydrogenase / genetics*
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Aldehyde Dehydrogenase / metabolism
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Aldehyde Dehydrogenase 1 Family
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Animals
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Antineoplastic Agents / pharmacology
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Cell Cycle / genetics
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Cell Line, Tumor
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Cisplatin / pharmacology
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics*
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Lung Neoplasms / mortality
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Lung Neoplasms / pathology
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Male
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Mice
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Middle Aged
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NFATC Transcription Factors / antagonists & inhibitors
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NFATC Transcription Factors / genetics*
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NFATC Transcription Factors / metabolism
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Neoplasm Grading
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Neoplasm Staging
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Phenotype
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Retinal Dehydrogenase
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SOXB1 Transcription Factors / genetics*
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SOXB1 Transcription Factors / metabolism
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Signal Transduction
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Survival Analysis
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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NFATC Transcription Factors
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NFATC2 protein, human
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RNA, Small Interfering
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SOX2 protein, human
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SOXB1 Transcription Factors
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Aldehyde Dehydrogenase 1 Family
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Aldehyde Dehydrogenase
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ALDH1A1 protein, human
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Retinal Dehydrogenase
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Cisplatin
Grants and funding
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.