| Summary: | 碩士 === 國立成功大學 === 臨床醫學研究所 === 102 === Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract. KIT, a receptor tyrosine kinase, is expressed in the most of GISTs (95%). Binding of the stem cell factor (SCF), the ligand of KIT, activate downstream signaling pathways, including MAPK, AKT, STAT1, and STAT3. In GISTs, about 65% of mutations occur in KIT exon 11, and it has been demonstrated that deletions in KIT exon 11 are associated with more malignant features and poor prognosis. Malignant GISTs commonly metastasize into liver (50–60%). However, the correlation between KIT mutations pattern and liver metastasis in GISTs is still unclear. Here, we purposed to examine the correlation between the KIT exon 11 deletion and liver metastasis behavior in GISTs. In our clinical data, the deletion in KIT exon 11 Trp-557 and Lys-558 was the most common mutation among KIT exon 11 mutations in GISTs with liver metastasis. ETV1, a transcription factor, participates in tumor invasion by activating the transcription of several genes. Previous studies have reported that ETV1 is highly expressed and regulated by activated KIT in GIST cells. The chemokine receptor CXCR4 has been reported to play a central role in tumor metastasis. In our study, we showed that KIT exon 11 557-558 deletion enhanced cell invasiveness and increased the expressions of ETV1 and CXCR4. In clinical GIST specimens, ETV1 and CXCR4 were closely associated with liver metastasis and KIT exon 11 deletion. The CXCR4 ligand CXCL12 is strongly expressed in liver, the most common metastatic site for GISTs. In vitro results show that KIT exon 11 557-558 deletion in GIST cells mediated chemotactic and invasive responses toward CXCL12 gradient. Inhibition of ETV1 and CXCR4 abrogated the effects. In vivo results show that KIT exon 11 557-558 deletion enhanced the liver metastatic potential of GIST cells. These findings indicate that CXCL12, highly expressed in liver, played as a chemoattractant that attract CXCR4-expressed tumor cells towards liver. In addition, we also found that ETV1 is able to directly bind to CXCR4 promoter in GIST cells with KIT exon 11 557-558 deletion by chromatin immunoprecipitation assay. In conclusion, KIT exon 11 557-558 deletion upregulated the expression of CXCR4 through the enhanced binding of ETV1 to CXCR4 promoter, and thus promoted liver metastasis via CXCL12/CXCR4axis. Our study provides insight that inhibition of the transcription activity of ETV1 and blockade of the CXCL12/CXCR4 axis may be a novel anti-metastatic therapy in GISTs.
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