Abstract
The glycolytic enzyme hexokinase (HK2), which is aberrantly expressed in various types of tumours, is associated with metastasis. However, its role in the progression and metastasis of tongue squamous cell carcinoma (TSCC) remains unclear. The results of our study showed that HK2 expression is often deregulated in TSCC patients. Increased HK2 expression was associated with tumour stage, clinical stage, lymph node metastasis, but not pathological grade, and reduced overall survival. Microarray and western blotting analyses revealed increases in HK2 expression in TSCC cells with higher metastatic potential. The following effects were observed with HK2 knockdown: inhibition of cell migration and invasion; reduced SOD2 activity and intracellular H2O2 levels; suppression of pERK1/2, Slug and Vimentin expression; and inhibition of tumour growth and lung metastasis in vivo. Conversely, HK2 overexpression promoted cell migration and invasion, increased SOD2 activity and intracellular H2O2, and enhanced expression of pERK1/2, Slug and Vimentin. Thus, our results demonstrate that deregulation of HK2 expression has an important function in the progression of TSCC and may serve as a biomarker of its metastatic potential in TSCC patients. HK2 enhances the metastatic potential of TSCC by stimulating the SOD2-H2O2 pathway.
Highlights
In contrast to normal cells, most cancer cells rely on glycolysis, even under normoxic conditions; this is a metabolic phenomenon called the Warburg effect [1]
Deregulated HK2 expression is associated with the development of tongue squamous cell carcinoma (TSCC) and prognosis of TSCC patients
Many studies have reported a high level of HK2 expression in cancer cells, and this has been associated with the risk of metastasis and poor prognosis [3, 5, 7, 20]
Summary
In contrast to normal cells, most cancer cells rely on glycolysis, even under normoxic conditions; this is a metabolic phenomenon called the Warburg effect [1]. Hexokinase (HK) catalyses the essentially irreversible first step of the glycolytic pathway, whereby glucose is phosphorylated to form glucose-6-phosphate As this product subsequently enters the glycolytic, oxidative phosphorylation (OXPHOS) or pentose phosphate pathway, HK is involved in almost all glucose metabolic processes [2]. Most normal mammalian tissues express very little HK2 [4]. Patra et al reported that HK2 plays an important role in tumour initiation and maintenance and that the HK2 gene can be systemically deleted without adverse physiological consequences. These findings suggest that HK2 deletion is an attractive potential therapeutic intervention for cancer patients [6]. Grimm et al showed that HK2 expression was significantly increased during OSCC development [8]
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