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

Qilin Xu,Yasutaka Ishida,Haoran Shi,Anh D Le,Xudong Tang,Chi V Dang,Qunzhou Zhang,Souren Hajjar

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.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is one of the 10 most common cancers in the world with more than half a million new cases per year globally, while oral squamous cell carcinoma (OSCC) represents the majority of head and neck squamous cell carcinomas (HNSCC) with ~25,000 new cases diagnosed each year in the U.S alone [1]
Our results showed that epidermal growth factor (EGF) induces epithelial-mesenchymal transition (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 Cancer stem cells (CSCs)-related genes, aldehyde dehydrogenase-1 (ALDH1) and Bmi-1
Knocking down the expression of Slug and Zeb1 partially abrogated the downregulation of E-cadherin expression and completely abolished the upregulation of vimentin expression induced by EGF in SCC-1 cells (Supplementary Figure 2), suggesting that Slug and Zeb1 contribute to EGF-induced EMT process in SCC-1 cells

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is one of the 10 most common cancers in the world with more than half a million new cases per year globally, while oral squamous cell carcinoma (OSCC) represents the majority of HNSCC with ~25,000 new cases diagnosed each year in the U.S alone [1]. Over half of the patients with head and neck cancer present with locally advanced disease manifested as regional and distant metastases, which contributes to a considerable proportion of the treatment failures and a ~50% reduction of survival rates [2–4). The 5-year survival still remains disappointing and most of the patients with recurrent or metastatic disease die within a year [4, 5]. Epidermal growth factor receptor (EGFR) is a member of the ERBB family of cell-surface tyrosine kinases [6]. It has been reported that more than 90% of head and neck squamous cell carcinomas (HNSCC) overexpress epidermal growth factor receptors (EGFRs), which play an important role in tumor progression and treatment resistance and emerge as important targets for the treatment of HNSCC [4, 7]. EGFR-targeted therapies are usually combined with either chemo- or radiation therapies due to the unsatisfactory response rates (~13%) as a monotherapy [11, 12]

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Results

Conclusion