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.
Highlights
Lung cancer results from mutations induced by DNA adducts, free radicals and reactive oxygen species (ROS) generated during tobacco smoking and chronic inflammation (Acharya et al, 2010; Okumura et al, 2012; Houghton, 2013)
Using log rank test and Kaplan-Meier survival analysis, we showed tumors with high level NFATc2 expression had significantly shorter recurrence-free survival (RFS) and cancer-specific overall survival (OS) (Figure 1E,F)
Multivariate Cox regression analysis further showed high NFATc2, late pathological stage, age and smoking history were independent prognostic indicators for shorter OS, while high NFATc2 and advanced pathological stage were predictive for shorter RFS (Table 1B, C)
Summary
Lung cancer results from mutations induced by DNA adducts, free radicals and reactive oxygen species (ROS) generated during tobacco smoking and chronic inflammation (Acharya et al, 2010; Okumura et al, 2012; Houghton, 2013). Recent research has shown the cellular landscape of a cancer is heterogeneous. Cells showing aberrant expressions of various molecules have enhanced propensities for survival, tumorigenicity, drug resistance, designated as cancer stem cells or tumor-initiating cells (TIC). Constitutive activities of inherent embryonic or developmental pathways for stem cell renewal are involved in TIC maintenance, such as the WNT/b-catenin pathway in colonic adenocarcinomas (AD). In tissues with slow cell turnover, mechanisms that elicit cell plasticity and stemness properties during tissue response to intracellular and extracellular stresses are involved (Valent et al, 2012; Visvader and Lindeman, 2012; Beck and Blanpain, 2013). Stem cell niches or their physiological regulatory mechanisms are ill-defined, and molecular programs sustaining lung TIC are still elusive
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