FGF19/SOCE/NFATc2 Signaling Circuit Facilitates the Self-renewal of Liver Cancer Stem Cells

Overview

Journal Theranostics

Date 2021 Mar 23

PMID 33754043

Citations 21

Authors

Jingchun Wang

Huakan Zhao

Lu Zheng

Yu Zhou

Lei Wu

Yanquan Xu

Xiao Zhang

Guifang Yan

Halei Sheng

Rong Xin

Lu Jiang

Juan Lei

Jiangang Zhang

Yu Chen

Jin Peng

Qian Chen

Shuai Yang

Kun Yu

Dingshan Li

Qichao Xie

Yongsheng Li

Affiliations

Soon will be listed here.

Abstract

Liver cancer stem cells (LCSCs) mediate therapeutic resistance and correlate with poor outcomes in patients with hepatocellular carcinoma (HCC). Fibroblast growth factor (FGF)-19 is a crucial oncogenic driver gene in HCC and correlates with poor prognosis. However, whether FGF19 signaling regulates the self-renewal of LCSCs is unknown. LCSCs were enriched by serum-free suspension. Self-renewal of LCSCs were characterized by sphere formation assay, clonogenicity assay, sorafenib resistance assay and tumorigenic potential assays. Ca image was employed to determine the intracellular concentration of Ca. Gain- and loss-of function studies were applied to explore the role of FGF19 signaling in the self-renewal of LCSCs. FGF19 was up-regulated in LCSCs, and positively correlated with certain self-renewal related genes in HCC. Silencing FGF19 suppressed self-renewal of LCSCs, whereas overexpressing FGF19 facilitated CSCs-like properties activation of FGF receptor (FGFR)-4 in none-LCSCs. Mechanistically, FGF19/FGFR4 signaling stimulated store-operated Ca entry (SOCE) through both the PLCγ and ERK1/2 pathways. Subsequently, SOCE-calcineurin signaling promoted the activation and translocation of nuclear factors of activated T cells (NFAT)-c2, which transcriptionally activated the expression of stemness-related genes (, and ), as well as . Furthermore, blockade of FGF19/FGFR4-NFATc2 signaling observably suppressed the self-renewal of LCSCs. FGF19/FGFR4 axis promotes the self-renewal of LCSCs activating SOCE/NFATc2 pathway; in turn, NFATc2 transcriptionally activates FGF19 expression. Targeting this signaling circuit represents a potential strategy for improving the therapeutic efficacy of HCC.

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