Kit exon 11 codons 557-558 deletion mutation promotes liver metastasis through the CXCL12/ CXCR4 Axis in gastrointestinal stromal tumors

Hao Chen Wang, Tzu Ying Li, Ying Jui Chao, Ya Chin Hou, Yuan Shuo Hsueh, Kai Hsi Hsu, Yan Shen Shan

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7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3477-3487
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number14
DOIs
Publication statusPublished - 2016 Jul 15

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Gastrointestinal Stromal Tumors
Sequence Deletion
Codon
Exons
Stromal Cells
Neoplasm Metastasis
Liver
Mutation
Cell Movement
Up-Regulation
Chromatin Immunoprecipitation
Research Design
Immunohistochemistry
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

@article{89bdaab624c34de9a5352dbd6d06a448,
title = "Kit exon 11 codons 557-558 deletion mutation promotes liver metastasis through the CXCL12/ CXCR4 Axis in gastrointestinal stromal tumors",
abstract = "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.",
author = "Wang, {Hao Chen} and Li, {Tzu Ying} and Chao, {Ying Jui} and Hou, {Ya Chin} and Hsueh, {Yuan Shuo} and Hsu, {Kai Hsi} and Shan, {Yan Shen}",
year = "2016",
month = "7",
day = "15",
doi = "10.1158/1078-0432.CCR-15-2748",
language = "English",
volume = "22",
pages = "3477--3487",
journal = "Clinical Cancer Research",
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TY - JOUR

T1 - Kit exon 11 codons 557-558 deletion mutation promotes liver metastasis through the CXCL12/ CXCR4 Axis in gastrointestinal stromal tumors

AU - Wang, Hao Chen

AU - Li, Tzu Ying

AU - Chao, Ying Jui

AU - Hou, Ya Chin

AU - Hsueh, Yuan Shuo

AU - Hsu, Kai Hsi

AU - Shan, Yan Shen

PY - 2016/7/15

Y1 - 2016/7/15

N2 - 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.

AB - 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.

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U2 - 10.1158/1078-0432.CCR-15-2748

DO - 10.1158/1078-0432.CCR-15-2748

M3 - Article

C2 - 26936919

AN - SCOPUS:84978533791

VL - 22

SP - 3477

EP - 3487

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 14

ER -