1. Academic Validation
  2. FGF19/SOCE/NFATc2 signaling circuit facilitates the self-renewal of liver cancer stem cells

FGF19/SOCE/NFATc2 signaling circuit facilitates the self-renewal of liver cancer stem cells

  • Theranostics. 2021 Mar 5;11(10):5045-5060. doi: 10.7150/thno.56369.
Jingchun Wang 1 Huakan Zhao 2 Lu Zheng 3 Yu Zhou 2 Lei Wu 2 Yanquan Xu 1 Xiao Zhang 1 Guifang Yan 2 Halei Sheng 1 Rong Xin 1 Lu Jiang 1 Juan Lei 2 Jiangang Zhang 1 Yu Chen 2 Jin Peng 1 Qian Chen 1 Shuai Yang 1 Kun Yu 1 Dingshan Li 1 Qichao Xie 4 Yongsheng Li 1 2
Affiliations

Affiliations

  • 1 Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
  • 2 Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing 400030, China.
  • 3 Department of Hepatobiliary Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
  • 4 Department of Oncology, The Third Affiliated Hospital, Chongqing Medical University, Chongqing 401120, China.
Abstract

Background & Aims: 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. Methods: 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. Ca2+ image was employed to determine the intracellular concentration of Ca2+. Gain- and loss-of function studies were applied to explore the role of FGF19 signaling in the self-renewal of LCSCs. Results: 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 via activation of FGF receptor (FGFR)-4 in none-LCSCs. Mechanistically, FGF19/FGFR4 signaling stimulated store-operated Ca2+ 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 (e.g., NANOG, OCT4 and SOX2), as well as FGF19. Furthermore, blockade of FGF19/FGFR4-NFATc2 signaling observably suppressed the self-renewal of LCSCs. Conclusions: FGF19/FGFR4 axis promotes the self-renewal of LCSCs via 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.

Keywords

FGF19; NFATc2, LCSCs; SOCE; self-renewal.

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