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

Wang, Jingchun; Zhao, Huakan; Zhou, Yu; Wu, Lei; Xu, Yanquan; Zhang, Xiao; Sheng, Halei; Rong, Xianglu; Jiang, Lu; Lei, Juan; Zhang, Jian Gang; Chen, Yu; Peng, Jin; Chen, Qian; Yang, Shuai; Yu, Kun; Li, Dingshan; Xie, Qiang; Li, Yongsheng

doi:10.7150/thno.56369

Cited by 35 publications

(23 citation statements)

References 59 publications

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“…Interestingly, a recent study identified Ca 2+ as a guardian of pluripotency in embryonic stem cells [ 56 ]. Our present demonstration of a role for SOC in GSC consolidates the idea that Ca 2+ may be essential for stemness, and further suggests that SOC represent an essential Ca 2+ handling mechanism involved in stemness maintenance, in both physiological and cancer stem cells [ 17 , 53 , 54 , 57 ]. SOC-mediated Ca 2+ entry has been identified to activate Ca 2+/ calmodulin-dependent protein kinase II (CaMKII) as well as well as NFAT [ 58 , 59 , 60 , 61 ].…”

Section: Discussionsupporting

confidence: 82%

“…As SKF-96365 and YM-58483 may also target other receptor channels (ROC), GSK-7975A, a more specific inhibitor of Orai-dependent SOCE was used [ 50 , 51 , 52 ]. The fact that GSK-7975A had also significant effects on GSC supports the idea that SOC play a key role in maintaining the GSC pool in GBM as they do in oral/oropharyngeal squamous cell carcinoma cancer stem cells and in liver cancer stem cells [ 53 , 54 ]. How SOC maintain the cancer stem cell population remains unknown.…”

Section: Discussionmentioning

confidence: 79%

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Store-Operated Calcium Channels Control Proliferation and Self-Renewal of Cancer Stem Cells from Glioblastoma

Terrié

Déliot

Benzidane

et al. 2021

Cancers

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Glioblastoma is the most frequent and deadly form of primary brain tumors. Despite multimodal treatment, more than 90% of patients experience tumor recurrence. Glioblastoma contains a small population of cells, called glioblastoma stem cells (GSC) that are highly resistant to treatment and endowed with the ability to regenerate the tumor, which accounts for tumor recurrence. Transcriptomic studies disclosed an enrichment of calcium (Ca2+) signaling transcripts in GSC. In non-excitable cells, store-operated channels (SOC) represent a major route of Ca2+ influx. As SOC regulate the self-renewal of adult neural stem cells that are possible cells of origin of GSC, we analyzed the roles of SOC in cultures of GSC previously derived from five different glioblastoma surgical specimens. Immunoblotting and immunocytochemistry experiments showed that GSC express Orai1 and TRPC1, two core SOC proteins, along with their activator STIM1. Ca2+ imaging demonstrated that SOC support Ca2+ entries in GSC. Pharmacological inhibition of SOC-dependent Ca2+ entries decreased proliferation, impaired self-renewal, and reduced expression of the stem cell marker SOX2 in GSC. Our data showing the ability of SOC inhibitors to impede GSC self-renewal paves the way for a strategy to target the cells considered responsible for conveying resistance to treatment and tumor relapse.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 79%

Store-Operated Calcium Channels Control Proliferation and Self-Renewal of Cancer Stem Cells from Glioblastoma

Terrié

Déliot

Benzidane

et al. 2021

Cancers

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“…In addition, recent evidence suggests that the formation of a complex of these proteins with phosphatase calcineurin dephosphorylates cytoplasmic NFAT and induces nuclear translocation. Nuclear NFAT transcriptionally activates the expression of several genes including NANOG, OCT4, SOX2, and FGF19 which are involved in cancer cell stemness ( Wang et al, 2021 ). In the current study, we conducted the gene ontology analysis, as a preliminary analysis to show the involvement of SOCs in the regulation of IP3 and ATPase pathways.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Genes Regulating Store-operated Calcium Entry in Conjunction With Mitochondrial Dynamics as Potential Biomarkers for Cancer: A Single-Cell RNA Analysis

et al. 2022

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Regulation of intracellular concentration of calcium levels is crucial for cell signaling, homeostasis, and in the pathology of diseases including cancer. Agonist-induced entry of calcium ions into the non-excitable cells is mediated by store-operated calcium channels (SOCs). This pathway is activated by the release of calcium ions from the endoplasmic reticulum and further regulated by the calcium uptake through mitochondria leading to calcium-dependent inactivation of calcium-release activated calcium channels (CARC). SOCs including stromal interaction molecules (STIM) and ORAI proteins have been implicated in tumor growth, progression, and metastasis. In the present study, we analyzed the mRNA and protein expression of genes mediating SOCs—STIM1, STIM2, ORAI1, ORAI2, ORAI3, TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, TRPC7, TRPV1, TRPV2, TRPM1, and TRPM7 in head and neck squamous cell cancer (HNSC) patients using TCGA and CPTAC analysis. Further, our in silico analysis showed a significant correlation between the expression of SOCs and genes involved in the mitochondrial dynamics (MDGs) both at mRNA and protein levels. Protein-protein docking results showed lower binding energy for SOCs with MDGs. Subsequently, we validated these results using gene expression and single-cell RNA sequencing datasets retrieved from Gene Expression Omnibus (GEO). Single-cell gene expression analysis of HNSC tumor tissues revealed that SOCs expression is remarkably associated with the MDGs expression in both cancer and fibroblast cells.

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“…Luo et al (9) revealed that the non-tumorigenic FGF19 variant effectively prevented and treated cholestasis liver disease and other diseases associated with bile acid dysregulation. Moreover, some studies demonstrated that FGF19 was a crucial oncogenic driver gene in HCC and correlated with poor prognosis (10)(11)(12)(13). In addition, Wu et al (14) pointed out that small proteins of hepatitis B virus surface antigen (SHBs) could activate the FGF19/JAK2/STAT3 signaling pathway through endoplasmic reticulum stress and induce epithelial-mesenchymal transformation process in HCC cells, thereby significantly increasing migration and invasion capacity of HCC cells.…”

Section: Introductionmentioning

confidence: 99%

Serum Fibroblast Growth Factor 19 as a Biomarker in Hepatitis B Virus-Related Liver Disease

Miao

et al. 2022

Hepat Mon

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Background: Past research has found that fibroblast growth factor 19 (FGF19) is associated with several hepatic disorders, such as alcoholic liver disease and primary biliary cirrhosis. However, there is currently a lack of relevant studies on the relationship between FGF19 and hepatitis B virus (HBV)-related liver disease. Objectives: This study aimed to assess the role of serum FGF19 as a new biomarker for HBV-related liver disease and provide scientific data to show the clinical value of this biomarker. Methods: A retrospective study included 37 patients with chronic hepatitis B (CHB), 33 patients with HBV-related cirrhosis (HBV-cirrhosis), and 32 patients with HBV-related hepatocellular carcinoma (HBV-HCC). Furthermore, 33 normal people were randomly selected as healthy controls. The serum levels of FGF19 were measured by ELISA. Results: Serum FGF19 levels were increased sequentially in the CHB group, HBV-cirrhosis group, and HBV-HCC group. Furthermore, serum FGF19 levels positively correlated with alpha-fetoprotein, prothrombin time, international normalized ratio, total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl-transferase, alkaline phosphatase, total bile acid, serum markers for liver fibrosis, ascites, cirrhosis, Child-Pugh classification and model for end-stage liver disease sodium (MELD-Na) score, while negatively correlated with platelet count, prothrombin activity, and albumin. The diagnostic threshold of serum FGF19 for HBV-related HCC was 165.32 pg/mL, with a sensitivity of 81.25% and specificity of 58.57%. Conclusions: Serum FGF19 levels are positively associated with cholestasis, hepatocyte damage, and liver fibrosis but negatively correlated with liver synthetic function and liver functional reserve in HBV-related liver disease. Diverse changes in serum FGF19 may be used as a predictive marker for the progression of HBV-related liver disease. In addition, serum FGF19 has a potential role in monitoring carcinogenesis in patients with HBV-related liver disease.

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

Cited by 35 publications

References 59 publications

Store-Operated Calcium Channels Control Proliferation and Self-Renewal of Cancer Stem Cells from Glioblastoma

Store-Operated Calcium Channels Control Proliferation and Self-Renewal of Cancer Stem Cells from Glioblastoma

Differential Expression of Genes Regulating Store-operated Calcium Entry in Conjunction With Mitochondrial Dynamics as Potential Biomarkers for Cancer: A Single-Cell RNA Analysis

Serum Fibroblast Growth Factor 19 as a Biomarker in Hepatitis B Virus-Related Liver Disease

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