Departmental Papers (Dental)

Document Type

Journal Article

Date of this Version

2017

Publication Source

Oncotarget

Volume

8

Issue

6

Start Page

9557

Last Page

9571

DOI

10.18632/oncotarget.13771

Abstract

"Warburg effect", the enhanced glycolysis or aerobic glycolysis, confers cancer cells the ability to survive and proliferate even under stressed conditions. In this study, we explored the role of epidermal growth factor (EGF) in orchestrating Warburg effect, the epithelial-mesenchymal transition (EMT) process, and the acquisition of cancer stem-like cell properties in human oral squamous cell carcinoma (OSCC) cells. Our results showed that EGF induces EMT process in OSCC cells, which correlates with the acquisition of cancer stem-like properties, including the enrichment of CD44+/CD24-population of cancer cells and an increased expression of CSC-related genes, aldehyde dehydrogenase-1 (ALDH1) and Bmi-1. We also showed that EGF concomitantly enhanced L-lactate production, while blocking glycolysis by 2-deoxy-D-glucose (2-DG) robustly reversed EGF-induced EMT process and CSC-like properties in OSCC cells. Mechanistically, we demonstrated that EGF promoted EMT process and CSC generation through EGFR/PI3K/HIF-1α axis-orchestrated glycolysis. Using an orthotopic tumor model of human OSCC (UM-SCC1) injected in the tongue of BALB/c nude mice, we showed that treatment with 2-DG in vivo significantly inhibited the metastasis of tumor cells to the regional cervical lymph nodes and reduced the expression of ALDH1 and vimentin in both in situ tumors and tumor cell-invaded regional lymph nodes. Taken together, these findings have unveiled a new mechanism that EGF drives OSCC metastasis through induction of EMT process and CSC generation, which is driven by an enhanced glycolytic metabolic program in OSCC cells.

Comments

Journal not peer-reviewed

Keywords

Cancer stem cells, EGF, EMT, Oral cancer, Warburg effect, aldehyde dehydrogenase isoenzyme 1, BMI1 protein, CD24 antigen, deoxyglucose, epidermal growth factor, epidermal growth factor receptor, Hermes antigen, hypoxia inducible factor 1alpha, lactic acid, phosphatidylinositol 3 kinase, aldehyde dehydrogenase 1 gene, animal experiment, animal model, animal tissue, Article, Bmi 1 gene, cancer stem cell, carcinogenesis, cell invasion, cervical lymph node metastasis, controlled study, disease activity, epithelial mesenchymal transition, female, glycolysis, human, human cell, in vivo study, lymph node metastasis, molecular dynamics, molecular pathology, mouse, mouth squamous cell carcinoma, nonhuman, oncogene, oral cancer cell line, oral squamous cell carcinoma cell line, protein determination, protein expression, protein function, tumor invasion, Warburg effect

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Date Posted: 10 February 2023