EGF induces epithelial-mesenchymal transition and cancer stem-like cell properties in human oral cancer cells via promoting Warburg effect

• DOI: 10.18632/oncotarget.13771
• Publication Date: 2016-12-03T23:13:12Z
• Authors: Qilin Xu; Qunzhou Zhang; Yasutaka Ishida; Souren Hajjar; Xudong Tang; Haoran Shi; Chi V. Dang; Anh D. Le
• Keywords: 0301 basic medicine; aldehyde dehydrogenase 1 gene; epithelial mesenchymal transition; oral squamous cell carcinoma cell line; deoxyglucose; BMI1 protein; molecular pathology; oncogene; oral cancer cell line; phosphatidylinositol 3 kinase; Hermes antigen; Mice, Inbred BALB C; lymph node metastasis; Cancer stem cells; Oral and Maxillofacial Surgery; Oral cancer; EMT; glycolysis; protein function; cell invasion; Bmi 1 gene; 3. Good health; ErbB Receptors; Isoenzymes; epidermal growth factor; female; Hyaluronan Receptors; Head and Neck Neoplasms; Carcinoma, Squamous Cell; cervical lymph node metastasis; Female; carcinogenesis; Glycolysis; Research Paper; CD24 antigen; cancer stem cell; Epithelial-Mesenchymal Transition; animal experiment; 610; Antineoplastic Agents; Deoxyglucose; Article; Aldehyde Dehydrogenase 1 Family; animal tissue; in vivo study; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; controlled study; hypoxia inducible factor 1alpha; human; Lactic Acid; protein expression; mouse; mouth squamous cell carcinoma; EGF; Oral Biology and Oral Pathology; nonhuman; Dose-Response Relationship, Drug; Epidermal Growth Factor; animal model; human cell; lactic acid; CD24 Antigen; aldehyde dehydrogenase isoenzyme 1; tumor invasion; Hypoxia-Inducible Factor 1, alpha Subunit; molecular dynamics; Dentistry; Warburg effect; epidermal growth factor receptor; disease activity; protein determination

"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.