1 FGF19/SOCE/NFATc2 signaling circuit facilitates the self- 2 renewal of liver cancer stem cells 3 4 Jingchun Wang 1†, Huakan Zhao2†*, Lu Zheng3†, Yu Zhou2, Lei Wu2, Yanquan Xu1, Xiao 5 Zhang1, Guifang Yan2, Halei Sheng1, Rong Xin1, Lu Jiang1, Juan Lei2, Jiangang Zhang1, Yu 6 Chen2, Jin Peng1, Qian Chen1, Shuai Yang1, Kun Yu1, Dingshan Li1, Qichao Xie4*, 7 Yongsheng Li1,2* 8 9 1Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, 10 Chongqing 400037, China. 11 2Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing 12 400030, China. 13 3Department of Hepatobiliary Surgery, Xinqiao Hospital, Army Medical University, 14 Chongqing 400037, China. 15 4Department of Oncology, The Third Affiliated Hospital, Chongqing Medical University, 16 Chongqing 401120, China 17 18 †These authors contributed equal to this work. 19 *Correspondence (
[email protected]) (H.Z.), (
[email protected]) (Q.X.), 20 (
[email protected]) (Y.L.). 21 22 Running title: FGF19-NFATc2 signaling promotes self-renewal of LCSCs. 23 Keywords: FGF19; Self-renewal; SOCE; NFATc2, LCSCs 24 1 25 Abstract 26 Background & Aims: Liver cancer stem cells (LCSCs) mediate therapeutic resistance and 27 correlate with poor outcomes in patients with hepatocellular carcinoma (HCC). Fibroblast 28 growth factor (FGF)-19 is a crucial oncogenic driver gene in HCC and correlates with poor 29 prognosis. However, whether FGF19 signaling regulates the self-renewal of LCSCs is 30 unknown. 31 Methods: LCSCs were enriched by serum-free suspension. Self-renewal of LCSCs were 32 characterized by sphere formation assay, clonogenicity assay, sorafenib resistance assay and 33 tumorigenic potential assays.