Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
Elife. 2017 Jul 24;6:e26733. doi: 10.7554/eLife.26733.
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 , 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.
肿瘤起始细胞（TIC）是具有增强肿瘤功能和对治疗有更强抵抗力的肿瘤细胞亚群，但肺癌中 TIC 的诱导或维持机制尚未完全清楚。在这项研究中，我们发现钙通路转录因子 NFATc2 是肺 TIC 表型的一个新的调控因子，包括肿瘤球、细胞迁移、致瘤性，以及对化疗和靶向治疗的体外和体内反应。在人类肺癌中，高 NFATc2 表达预示着肿瘤分化不良、无复发生存和癌症特异性总生存率不良。机制研究确定了 3'增强子区域中的 NFATc2 反应元件，NFATc2/SOX2 通过结合其 5'增强子偶联而上调 ALDH1A1。通过这个轴，癌症药物治疗引起的氧化应激被减弱，导致以不依赖于突变的方式增加耐药性。靶向这个轴为通过 TIC 消除来长期治疗肺癌提供了一种新方法。
