The role of novel fusion genes in human GIST cell lines derived from imatinib-resistant GIST patients: A therapeutic potential of fusion gene
| Autor: | Woo Cheol Cho, Ja-Lok Ku, Young Soon Na, Min Hee Ryu, Young Kyoung Shin, Yoon-Koo Kang |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncogene Proteins Fusion Gastrointestinal Stromal Tumors Biophysics Antineoplastic Agents PDGFRA Gene mutation Biology medicine.disease_cause Biochemistry Fusion gene 03 medical and health sciences Transduction (genetics) 0302 clinical medicine Cell Line Tumor medicine Humans neoplasms Molecular Biology Gene Cell Proliferation GiST Imatinib Cell Biology digestive system diseases 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Imatinib Mesylate Cancer research Carcinogenesis medicine.drug |
| Zdroj: | Biochemical and Biophysical Research Communications. 529:699-706 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2020.05.174 |
| Popis: | Gastrointestinal stromal tumor (GIST) is the most common sarcoma in the gastrointestinal (GI) tract. Approximately 85% of the GIST is associated with a c-KIT mutation. A few GISTs show mutations in the gene encoding platelet-derived growth factor receptor alpha (PDGFR α or PDGFRA) without c-KIT gene mutation. GIST without c-KIT or PDGFRA mutations, which called wild type GIST, is about 5-10% of the total GIST. Fusion genes were also reported as one of the factors associated with carcinogenesis and drug resistance. With five cell lines derived from imatinib-resistant patients, novel fusion genes were identified from RNA sequencing and both physiological role and therapeutic potential were elucidated. Next-generation sequencing (NGS) analysis and lentiviral transduction were used to effect of fusion gene on GISTs. All the GIST cell lines carried c-KIT-positivity. Three different fusion gene analysis methods were used to find candidate fusion genes, including EIF3K-ACTN4, SYNCRIP-SNX14 and EXOC2-AK7. A novel interchromosomal fusion gene of the candidates, especially EXOC2-AK7, was confirmed in both tissue and cell line. The transduction of fusion gene increased the proliferation compared with the control group. Additionally, the fusion gene increased wound coverage capability. The fusion gene-transduced cell lines were more sensitive than the control group in the treatment of imatinib. In conclusion, five different imatinib-resistant GIST cell lines including the EXOC2-AK7 fusion gene derived from GIST-R5 represent important research tools for the investigation of cancer cell mechanisms underlying drug resistance and genetic variation. Furthermore, our study may facilitate pre-clinical studies of new therapeutic strategies. |
| Databáze: | OpenAIRE |
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