https://scholars.lib.ntu.edu.tw/handle/123456789/470767
標題: | Oncogenic Function of a KIF5B-MET Fusion Variant in Non-Small Cell Lung Cancer | 作者: | Gow C.-H. Liu Y.-N. Li H.-Y. MIN-SHU HSIEH Chang S.-H. Luo S.-C. TZU-HSIU TSAI PEI-LUNG CHEN Tsai M.-F. JIN-YUAN SHIH |
公開日期: | 2018 | 出版社: | Neoplasia Press, Inc. | 卷: | 20 | 期: | 8 | 起(迄)頁: | 838-847 | 來源出版物: | Neoplasia (United States) | 摘要: | A kinesin family member 5b (KIF5B)-MET proto-oncogene, receptor tyrosine kinase (MET) rearrangement was reported in patients with lung adenocarcinoma but its oncogenic function was not fully evaluated. We used one-step reverse transcription-polymerase chain reaction for RNA samples to screen for the KIF5B-MET fusion in 206 lung adenocarcinoma and 28 pulmonary sarcomatoid carcinoma patients. Genomic breakpoints of KIF5B-MET were determined by targeted next-generation sequencing. Soft agar colony formation assays, proliferation assays, and a xenograft mouse model were used to investigate its oncogenic activity. In addition, specific MET inhibitors were administered to evaluate their anti-tumor activities. A KIF5B-MET fusion variant in a patient with a mixed-type adenocarcinoma and sarcomatoid tumor was identified, and another case was found in a pulmonary sarcomatoid carcinoma patient. Both cases carried the same chimeric gene, a fusion between exons 1–24 of KIF5B and exons 15–21 of MET. KIF5B-MET-overexpressing cells exhibited significantly increased proliferation and colony-forming ability. Xenograft tumors harboring the fusion gene demonstrated significantly elevated tumor growth. Ectopic expression of the fusion gene stimulated the phosphorylation of KIF5B-MET as well as downstream STAT3, AKT, and ERK1/2 signaling pathways. The MET inhibitors significantly repressed cell proliferation; phosphorylation of downstream STAT3, AKT, and ERK1/2; and xenograft tumorigenicity. In conclusion, the KIF5B-MET variant was demonstrated to have an oncogenic function in cancer cells. These findings have immediate clinical implications for the targeted therapy of subgroups of non-small cell lung cancer patients. ? 2018 The Authors |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85049745714&doi=10.1016%2fj.neo.2018.06.007&partnerID=40&md5=6de595fe11d42c133f32020fe7ecfe55 https://scholars.lib.ntu.edu.tw/handle/123456789/470767 |
ISSN: | 1522-8002 | DOI: | 10.1016/j.neo.2018.06.007 | SDG/關鍵字: | capmatinib; crizotinib; cytokeratin 7; homeobox protein Nkx 2.1; interleukin 3; mitogen activated protein kinase 1; mitogen activated protein kinase 3; protein kinase B; RNA; STAT3 protein; KIF5B protein, human; kinesin; oncoprotein; scatter factor receptor; animal experiment; animal model; animal tissue; antineoplastic activity; Article; cancer cell; cancer growth; cell proliferation; colony formation; colony forming unit; controlled study; drug megadose; ectopic expression; exon; fusion gene; genetic variability; genomics; KIF5B MET gene; low drug dose; lung adenocarcinoma; mouse; next generation sequencing; non small cell lung cancer; nonhuman; priority journal; reverse transcription polymerase chain reaction; Sanger sequencing; sarcomatoid carcinoma; signal transduction; Taiwanese; treatment response; adenocarcinoma; animal; Bagg albino mouse; carcinogenesis; cell line; gene translocation; genetic variation; genetics; HEK293 cell line; human; lung tumor; non small cell lung cancer; nude mouse; oncogene; Adenocarcinoma; Animals; Carcinogenesis; Carcinoma, Non-Small-Cell Lung; Cell Line; Cell Proliferation; Exons; Genetic Variation; HEK293 Cells; Humans; Kinesin; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Oncogene Proteins, Fusion; Oncogenes; Proto-Oncogene Proteins c-met; Translocation, Genetic |
顯示於: | 病理學科所 |
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