Epidermal growth factor signals regulate dihydropyrimidine dehydrogenase expression in EGFR-mutated non-small-cell lung cancer

BMC Cancer

Research Article

Kazuhiro Tsukamoto¹  Atsushi Nanashima²  Tetsuro Tominaga³  Junichi Arai³  Toshiya Nagasaki³  Takuro Miyazaki³  Koji Mochinaga³  Takeshi Nagayasu³  Tomoshi Tsuchiya³  Keitaro Matsumoto³  Naoya Yamasaki³ 

[1]Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Science, 1-14 Bunkyo, 852-8521, Nagasaki, Nagasaki, Japan

[2]Department of Surgery, Miyazaki University School of Medicine, 5200 Kihara, 889-1692, Miyazaki, Miyazaki, Japan

[3]Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, 852-8501, Nagasaki, Nagasaki, Japan

关键词: Non-small-cell lung cancer;    Sp1;    Dihydropyrimidine dehydrogenase;    Epidermal growth factor receptor mutation;    5-fluorouracil;   

DOI  :  10.1186/s12885-016-2392-0

 received in 2015-07-10, accepted in 2016-06-01,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundIt 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.MethodsWe 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.ResultsIn 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. Among EGFR-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.ConclusionsThe 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.

【 授权许可】

CC BY   
© The Author(s). 2016