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 D557-558) increased GIST cell motility and liver metastasis. Mechanistically, overexpression of KIT D557-558 in GIST cells increased ETV1 and CXCR4 expression. CXCR4 knockdown counteracted KIT D557-558-mediated cell migration. Moreover, KIT D557-558-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 D557-558 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.

Hepatitis B virus X protein promotes the stem-like properties of OV6+ cancer cells in hepatocellular carcinoma

“…20 The CXCL12/CXCR4 pathway has been implicated in various types of cancers. 34 Both the autocrine and paracrine effects of this pathway have been shown to maintain cancer growth and progression. 35 Therefore, we investigated whether HBx/MDM2 regulated the stemness of OV6 + CSCs through the CXCL12/CXCR4 pathway.…”

Genotype and risk of tumour rupture in gastrointestinal stromal tumour

“…It could be assumed that these tumours are growing faster and are more necrotic than tumours with other genotypes, resulting in a more fragile structure. Specific downstream signalling events are activated by del557/558, indicating that certain uncharacterized phenotypic changes that affect the likelihood of rupture may be induced by distinct KIT and PDGFRA mutations. In support of this hypothesis, del557/558 remained associated with rupture when size and mitotic count were included in a logistic regression analysis, suggesting an independent risk associated with this mutation.…”

KTN0158, a Humanized Anti-KIT Monoclonal Antibody, Demonstrates Biologic Activity against both Normal and Malignant Canine Mast Cells

“…However, MCT with KIT exon 11 mutations appeared to be particularly sensitive to KTN0158 (Figure 3c; Table 3). Importantly, exon 11 KIT mutations drive ligand-independent receptor dimerization and are associated with metastasis and poor prognosis in human GIST (43-45) and canine MCT (8, 14, 15). As such, the antitumor effects of KTN0158 in dogs with MCTs containing exon 11 KIT mutations suggest that KTN0158 may benefit patients with GISTs harboring similar mutations.…”