EGFR mutation decreases FDG uptake in non-small cell lung cancer via the NOX4/ROS/GLUT1 axis

[F-18]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) is a functional imaging modality based on glucose metabolism. The association between the maximum standardized uptake value (SUVmax) from F-18-FDG PET-CT scanning and epidermal growth factor receptor (EGFR) mutation status has, to the best of our knowledge, not previously been fully elucidated, and the potential mechanisms by which EGFR mutations alter FDG uptake are largely unknown. A total of 157 patients who were pathologically diagnosed with non-small cell lung cancer (NSCLC) who underwent EGFR mutation testing and PET-CT pretreatment between June 2015 and October 2017 were retrospectively analyzed. (2) and univariate analyses were performed to identify the contributors to EGFR mutation. The receiver operating characteristic (ROC) curve was analyzed, and the area under the curve (AUC) was calculated. Glucose transporter 1 (GLUT1) and NADPH oxidase 4 (NOX4) expression, and reactive oxygen species (ROS) activity were detected in the A549 (wild-type), PC-9 (EGFR mutation-positive, EGFR exon 19del) and NCI-H1975 (EGFR mutation-positive, combined with L858R and T790M substitution) cell lines. A total of 109 patients who met the criteria were enrolled, and 63 of those tested as EGFR mutation-positive. The SUVmax values were significantly lower in patients with EGFR mutations (mean, 6.52 +/- 0.38) compared with in patients with wild-type EGFR (mean, 9.37 +/- 0.31; P<0.001). Using univariate analysis, EGFR mutation status was significantly associated with sex, smoking status, tumor histology and SUVmax of the primary tumor. In the multivariate analysis, smoking status (never-smoking), histopathology (adenocarcinoma) and SUVmax (9.91) were the statistically significant predictors of EGFR mutations. ROC curve analysis identified that the SUVmax cut-off point was 9.92, for which the AUC was 0.75 (95% confidence interval, 0.68-0.83). Reverse transcription-polymerase chain reaction indicated that the GLUT1 mRNA decreased in the PC-9 and NCI-H1975 cell lines compared with the A549 cell line (0.82 +/- 0.07 and 0.72 +/- 0.04 vs. 0.98 +/- 0.04, respectively; P<0.05) and decreased ROS activity was observed in the PC-9 cell line. Furthermore, the expression of NOX4 mRNA decreased by 20% in PC-9 (P<0.01) and by 14% (P<0.05) in NCI-H1975 cells. In addition, NOX4 protein expression decreased by 13% in PC-9 and by 16% in NCI-H1975 cells (both P<0.05) compared with the A549 cell line. The SUVmax could be considered to effectively predict EGFR mutation status of patients with NSCLC, and the EGFR mutation status may alter FDG uptake partially via the NOX4/ROS/GLUT1 axis.