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




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BMC Cancer

, 16:354

Cell and molecular biology

Abstract

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.

KeywordsNon-small-cell lung cancer Sp1 Dihydropyrimidine dehydrogenase Epidermal growth factor receptor mutation 5-fluorouracil Electronic supplementary materialThe online version of this article doi:10.1186-s12885-016-2392-0 contains supplementary material, which is available to authorized users.

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Author: Tetsuro Tominaga - Tomoshi Tsuchiya - Koji Mochinaga - Junichi Arai - Naoya Yamasaki - Keitaro Matsumoto - Takuro Miyazaki

Source: https://link.springer.com/







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