KIT Exon 11 Codons 557-558 Deletion Mutation Promotes Liver Metastasis Through the CXCL12/CXCR4 Axis in Gastrointestinal Stromal Tumors
Autor: | Kai Hsi Hsu, Tzu Ying Li, Ya Chin Hou, Hao-Chen Wang, Yan Shen Shan, Yuan Shuo Hsueh, Ying Jui Chao |
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Rok vydání: | 2015 |
Předmět: |
0301 basic medicine
Male Cancer Research Receptors CXCR4 Stromal cell Gastrointestinal Stromal Tumors Mice SCID Biology medicine.disease_cause Metastasis 03 medical and health sciences Exon Mice 0302 clinical medicine Mice Inbred NOD Cell Line Tumor medicine Animals Humans Codon Sequence Deletion Mutation GiST Liver Neoplasms Exons medicine.disease Immunohistochemistry digestive system diseases Chemokine CXCL12 Proto-Oncogene Proteins c-kit 030104 developmental biology Oncology Liver 030220 oncology & carcinogenesis Cancer research Chromatin immunoprecipitation Signal Transduction |
Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 22(14) |
ISSN: | 1557-3265 |
Popis: | Purpose: KIT mutations, the most prevalent genetic event in gastrointestinal stromal tumors (GIST), 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: A total of 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 pharmacologic 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 Δ557–558) increased GIST cell motility and liver metastasis. Mechanistically, overexpression of KIT Δ557–558 in GIST cells increased ETV1 and CXCR4 expression. CXCR4 knockdown counteracted KIT Δ557–558–mediated cell migration. Moreover, KIT Δ557–558–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 Δ557–558 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. Clin Cancer Res; 22(14); 3477–87. ©2016 AACR. |
Databáze: | OpenAIRE |
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