國家衛生研究院 NHRI:Item 3990099045/12302
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    題名: ANGPTL4 induces TMZ resistance of glioblastoma by promoting cancer stemness enrichment via the EGFR/AKT/4E-BP1 cascade
    作者: Tsai, YT;Wu, AC;Yang, WB;Kao, TJ;Chuang, JY;Chang, WC;Hsu, TI
    貢獻者: NHRI Graduate Student Program
    摘要: Glioblastoma (GBM) is the most aggressive type of brain tumor, with strong invasiveness and a high tolerance to chemotherapy. Despite the current standard treatment combining temozolomide (TMZ) and radiotherapy, glioblastoma can be incurable due to drug resistance. The existence of glioma stem-like cells (GSCs) is considered the major reason for drug resistance. However, the mechanism of GSC enrichment remains unclear. Herein, we found that the expression and secretion of angiopoietin-like 4 protein (ANGPTL4) were clearly increased in GSCs. The overexpression of ANGPTL4 induced GSC enrichment that was characterized by polycomb complex protein BMI-1 and SRY (sex determining region Y)-box 2 (SOX2) expression, resulting in TMZ resistance in GBM. Furthermore, epidermal growth factor receptor (EGFR) phosphorylation induced 4E-BP1 phosphorylation that was required for ANGPTL4-induced GSC enrichment. In particular, ANGPTL4 induced 4E-BP1 phosphorylation by activating phosphoinositide 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) cascades for inducing stemness. To elucidate the mechanism contributing to ANGPTL4 upregulation in GSCs, chromatin immunoprecipitation coupled with sequencing (ChIP-Seq) revealed that specificity protein 4 (Sp4) was associated with the promoter region, -979 to -606, and the luciferase reporter assay revealed that Sp4 positively regulated activity of the ANGPTL4 promoter. Moreover, both ANGPTL4 and Sp4 were highly expressed in GBM and resulted in a poor prognosis. Taken together, Sp4-mediated ANGPTL4 upregulation induces GSC enrichment through the EGFR/AKT/4E-BP1 cascade.
    日期: 2019-11-11
    關聯: International Journal of Molecular Sciences. 2019 Nov 11;20(22):Article number 5625.
    Link to: http://dx.doi.org/10.3390/ijms20225625
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1422-0067&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000502786800107
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85074961457
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