國家衛生研究院 NHRI:Item 3990099045/9629
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    题名: KIT exon 11 codons 557-558 deletion mutation promotes liver metastasis through the CXCL12/CXCR4 axis in gastrointestinal stromal tumors
    作者: Wang, HC;Li, TY;Chao, YJ;Hou, YC;Hsueh, YS;Hsu, KH;Shan, YS
    贡献者: National Institute of Cancer Research
    摘要: PURPOSE: KIT mutations, the most prevalent genetic event in gastrointestinal stromal tumors (GISTs), are associated with malignant features and poor prognosis. Aggressive GISTs possess a high propensity to spread to the liver. This study aimed to explore the role of KIT mutations in GIST liver metastasis. EXPERIMENTAL DESIGN: 170 GISTs were used to determine the association between KIT mutations and liver metastasis. Immunohistochemistry was performed to assess the correlation of KIT mutations with CXCR4 and ETV1 expression. Genetic and pharmacological methods were used to study the regulation of CXCR4 and ETV1 by KIT mutations. RESULTS: Codons 557 and 558 in KIT exon 11 were deletion hot spots in GISTs. KIT exon 11 deletions involving codons 557-558 were highly associated with liver metastasis. Overexpression of mutant KIT with exon 11 codons 557-558 deletion (KIT big up tri, open557-558) increased GIST cell motility and liver metastasis. Mechanistically, overexpression of KIT big up tri, open557-558 in GIST cells increased ETV1 and CXCR4 expression. CXCR4 knockdown counteracted KIT big up tri, open557-558-mediated cell migration. Moreover, KIT big up tri, open557-558-induced CXCR4 expression could be abolished by silencing ETV1. The chromatin immunoprecipitation assay showed that ETV1 directly bound to the CXCR4 promoter. After ERK inhibitor PD325901 treatment, the upregulation of ETV1 by KIT big up tri, open557-558 was prevented. In addition, KIT exon 11 codons 557-558 deletion enhanced CXCL12-mediated GIST cell migration and invasion. CONCLUSIONS: KIT exon 11 557-558 deletion upregulates CXCR4 through increased binding of ETV1 to the CXCR4 promoter in GIST cells, which thus promotes liver metastasis. These findings highlighted the potential therapeutic targets for metastatic GISTs.
    日期: 2016-07
    關聯: Clinical Cancer Research. 2016 Jul;22(14):3477-3487.
    Link to: http://dx.doi.org/10.1158/1078-0432.ccr-15-2748
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1078-0432&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000381113000009
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84978533791
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