title: EGF induces epithelial-mesenchymal transition and cancer stem-like cell properties in human oral cancer cells via promoting Warburg effect.
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.
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Qilin
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Qunzhou
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.|Department of Molecular Oral Medicine and Maxillofacial Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Souren
authors.initials: S
authors.lastname: Hajjar
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.|Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Haoran
authors.initials: H
authors.lastname: Shi
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.|Department of Oral & Maxillofacial Surgery, Penn Medicine Hospital of The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Anh D
authors.initials: AD
authors.lastname: Le
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051927:CD24 Antigen / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism; D005260:Female; D006019:Glycolysis / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C069077:BMI1 protein, human; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; C497442:HIF1A protein, human; D018960:Hyaluronan Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D019344:Lactic Acid; D004815:Epidermal Growth Factor; D003847:Deoxyglucose; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D063150:Polycomb Repressive Complex 1; D058539:Phosphatidylinositol 3-Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGF; EMT; Warburg effect; cancer stem cells; oral cancer