The Effect of GLUT1 and HIF-1α Expressions on Glucose Uptake and Patient Survival in Non-Small-Cell Lung Carcinoma

Abstract

Lung cancer is the second-most-common cancer while being the leading cause of cancer deaths worldwide. It has been found that glucose transporter 1 (GLUT1) and hypoxia-inducible factor 1α (HIF-1α) are overexpressed in various malignancies and that they correlate with the maximum standard uptake values (SUVmax) on 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) and poor prognosis. In this study, we aim to evaluate the relationship between the SUVmax, GLUT1, and HIF-1α expression with primary tumor size, histological type, lymph node metastases, and patient survival. Of the 48 patients with non-small-cell lung cancer, those with squamous cell carcinomas (SCCs) had significantly higher GLUT1 and HIF-1α immunohistochemical expressions in comparison to adenocarcinomas (ACs), while there was no statistically significant difference in FDG accumulation between them. No significant correlation was noted between either GLUT1 or HIF-1α protein expression and FDG uptake and overall survival. However, an analysis of tumor transcriptomics showed a significant difference in overall survival depending on mRNA expression; patients with SCC and high HIF-1α levels survived longer compared to those with low HIF-1α levels, while patients with AC and low GLUT1 levels had a higher average survival time than those with high GLUT1 levels. Further studies are needed to determine the prognostic value of the expression of these factors depending on the histologic type.

Keywords: GLUT1; HIF-1α; PET CT; lung adenocarcinoma; lung squamous cell carcinoma.

Figure 1

Morphology and GLUT1 expression in lung carcinoma. Typical glandular morphology is observed in both primary (a) and metastatic lesions (c) of lung adenocarcinomas. Weak-to-no GLUT1 expression is seen in the primary adenocarcinoma lesion (b), while a mild, cytoplasmatic expression characterizes the metastasis (d). Morphology typical for squamous cell carcinomas is visible in primary (e) and metastatic lesions (g). Both lesions display strong, membranous GLUT1 expression in most of their tumor cells (f,h). Hematoxylin and eosin staining (a,c,e,g); immunohistochemical staining to GLUT1 (b,d,f,h). All images are taken at ×100 magnification; scale bars represent 200 µm.

Figure 2

HIF-1α protein expression in lung carcinoma. S1—stage I, S2—stage II, S3—stage III. Some cells of lung adenocarcinoma lesions display cytoplasmatic HIF-1α staining (arrows), while only a few cells display nuclear staining (arrowheads). Conversely, most cells of lung squamous cell carcinomas demonstrate strong nuclear HIF-1α staining (arrowheads). Immunofluorescent staining to HIF-1α; images are taken at ×400 total magnification; scale bars represent 100 µm. Graphs represent the mean value HIF-1α positive cells; error bars represent the standard deviation; ** p < 0.01.

Figure 3

Graphic representation of survival analysis (days) of HIF-1α and GLUT1 high (black line)- and low (red line)-mRNA-expression in lung ACs and SCCs. The Kaplan–Meier method and log-rank test were used for survival length. The data are used from the GDC TCGA Lung Adenocarcinoma (LUAD) and GDC TCGA Lung Squamous Cell Carcinoma (LUSC) studies.