Abstract
High expression of glucose transporter family members, which augment glucose uptake and glycolytic flux, has been shown to play a pivotal role in the proliferation and survival of tumor cells, contributing to the energy supply, biosynthesis and homeostasis of cancer cells. Among the many members, solute carrier family 2 member 1 (SLC2A1) encodes a glucose transporter, GLUT1, that is critical in the metabolism of glucose, which is an energy source for cell growth that contributes to cancer progression and development. The aim of this study was to analyze the survival and genetic changes/immune profiles in patients with gastric cancer with high SLC2A1 expression and to provide treatment for improving prognosis. This study investigated the clinicopathologic parameters, the proportion of immune cells and gene sets affecting SLC2A1 expression in 279 and 415 patients with gastric cancer from the Eulji Hospital cohort and The Cancer Genome Atlas, respectively. We assessed the response to conventional chemotherapy drugs, including fluorouracil, a compound of fluoropyrimidine S-1, oxaliplatin, and all-trans-retinoic acid (ATRA), in gastric cancer cell lines with high SLC2A1 expression. High SLC2A1 expression was associated with poor prognosis, cancer cell proliferation, decreased immune cells, including CD8 T cells and B cells, and a low prognostic nutrition index, representing body nutrition-related status. In pathway network analysis, SLC2A1 was indirectly linked to the retinoic signaling pathway and negatively regulated immune cells/receptors. In the drug response analysis, the drug ATRA inhibited gastric cancer cell lines with high SLC2A1 expression. Treatment involving the use of SLC2A1 could contribute to better clinical management/research for patients with gastric cancer.
Highlights
Cancer depends on glycolysis as well as oxidative phosphorylation for energy production, which can affect the proliferation and growth of tumor cells
We focused on evaluating SLC2A1-associated immune gene sets and genes, different types of tumor-infiltrating immune cells and network-based pathways as well as in vitro drug screening tests in gastric cancer cell lines
In pathway network analysis based on GSEA, we found that high SLC2A1 expression was indirectly linked to negative regulation of immune cells, B cell receptor (BCR) signaling, and the retinoic acid pathway (Fig 3E)
Summary
Cancer depends on glycolysis as well as oxidative phosphorylation for energy production, which can affect the proliferation and growth of tumor cells. Glucose transporter family members (GLUT114) are expressed in the membranes of most cell types [1, 2]. Among the many elements related to glucose metabolism, solute carrier family 2 member 1 (SLC2A1), a glucose transporter-encoding gene that controls glucose uptake, could play a pivotal role in the growth and proliferation of tumor cells [3, 4]. In a study by Warburg, tumor cells were seen to take up glucose at an elevated rate to meet their increased energy demands [5]. High expression of GLUT1, encoded by SLC2A1, is associated with different types of malignancies, especially those driven by oncogenic KRAS and BRAF mutations or loss of p53, and thereby contributes to the increased proliferation of cancer cells [7,8,9]. Previous studies demonstrated that high SLC2A1 expression was associated with worse prognosis in colon, lung, breast, and oral cancer [4, 9,10,11]
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