RT Journal Article
SR Electronic
T1 NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 131987
DO 10.1101/131987
A1 Zhi-Jie Xiao
A1 Jing Liu
A1 Si-Qi Wang
A1 Yun Zhu
A1 Xu-Yuan Gao
A1 Vicky Pui-Chi Tin
A1 Jing Qin
A1 Jun-Wen Wang
A1 Maria Pik Wong
YR 2017
UL http://biorxiv.org/content/early/2017/04/28/131987.abstract
AB Cancers display intratumoral genetic and molecular heterogeneity with tumor initiating cells (TIC) showing enhanced tumor phenotypes. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC through the NFATc2/SOX2/ALDH1A1 regulatory axis. In vitro and in vivo cancer cell modeling demonstrated supportive evidences including cell renewal, tumorigenicity at limiting dose, cell motility, resistance to cytotoxic chemotherapy and EGFR targeted therapy. In human lung cancers, high NFATc2 expression predicts poor tumor differentiation, adverse recurrence-free and overall patient survivals. Mechanistic investigations identified NFATc2 response elements in the SOX2 3’ enhancer region, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5’ enhancer. Through this axis, oxidative stresses and reactive oxygen species induced by cancer drug treatment are attenuated, accounting for a mutation-independent mechanism of drug resistance. Targeting this axis provides a novel approach for the long term treatment of lung cancer through TIC elimination.