並列タイトル等EGFR変異型非小細胞肺癌におけるEGFシグナルのDPD発現調整
授与機関名Nagasaki University (長崎大学)
一般注記Background: It has been shown that epidermal growth factor receptor (EGFR) mutation status is associated with 5-fluorouracil (5-FU) sensitivity in non-small-cell lung cancer (NSCLC). However, the relationship between EGFR mutation status and dihydropyrimidine dehydrogenase (DPD), a 5-FU degrading enzyme, is unknown. Methods: We elucidated the crosstalk among the EGFR signal cascade, the DPD gene (DPYD), and DPD protein expression via the transcription factor Sp1 and the effect of EGFR mutation status on the crosstalk. Results: In the PC9 (exon19 E746-A750) study, EGF treatment induced up-regulation of both Sp1 and DPD; gefitinib, an EGFR-tyrosine kinase inhibitor (EGFR-TKI), and mithramycin A, a specific Sp-1 inhibitor, suppressed them. AmongEGFR-mutated (PC9, HCC827; exon19 E746-A750 and H1975; exon21 L858R, T790M, gefitinib resistant) and -non-mutated (H1437, H1299) cell lines, EGF administration increased DPYD mRNA expression only in mutated cells(p < 0.05). Accordingly, gefitinib inhibited DPD protein expression only in PC9 and HCC827 cells, and mithramycin A inhibited it in EGFR-mutated cell lines, but not in wild-type. FU treatment decreased the level of cell viability more in gefitinib-treated EGFR-TKI sensitive cell lines. Further, combination treatment of FU and mithramycin A suppressed cell viability even in a gefitinib resistant cell line. Conclusions: The EGFR signal cascade regulates DPD expression via Sp1 in EGFR mutant cells. These results might be a step towards new therapies targeting Sp1 and DPD in NSCLC with different EGFR mutant status.
長崎大学学位論文 学位記番号:博(医歯薬)甲第886号 学位授与年月日:平成28年9月7日
Author: Tetsuro Tominaga, Tomoshi Tsuchiya, Koji Mochinaga, Junichi Arai, Naoya Yamasaki, Keitaro Matsumoto, Takuro Miyazaki, Toshiya Nagasaki, Atsushi Nanashima, Kazuhiro Tsukamoto, Takeshi Nagayasu
Citation: BMC Cancer, 16, 354; 2016
Nagasaki University (長崎大学), 博士(医学) (2016-09-07)
DOIinfo:doi/10.1186/s12885-016-2392-0
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