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

Abstract

// Qilin Xu 1 , Qunzhou Zhang 1 , Yasutaka Ishida 1, 2 , Souren Hajjar 1 , Xudong Tang 1, 3 , Haoran Shi 1 , Chi V. Dang 4 , Anh D. Le 1, 5 1 Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA 2 Department of Molecular Oral Medicine and Maxillofacial Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Japan 3 Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, Guangdong, China 4 Abramson Cancer Center, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA 5 Department of Oral & Maxillofacial Surgery, Penn Medicine Hospital of The University of Pennsylvania, Philadelphia, Pennsylvania, USA Correspondence to: Anh D. Le, email: Anh.Le@uphs.upenn.edu Keywords: EGF, EMT, cancer stem cells, Warburg effect, oral cancer Received: June 30, 2016     Accepted: November 21, 2016     Published: December 01, 2016 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.