Abstract
Background: Routine changes in cell metabolism can drive tumor development, as the cellular program develops to promote glycolysis and redox homeostasis during tumor progression; however, the associated mechanisms in tongue squamous cell carcinoma (TSCC) remain unclear.Methods: We investigated methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) expression, its clinical relevance, redox modification, and molecular mechanisms using TSCC cells and tissues. The anti-tumor effects of MTHFD1L knockdown on TSCC tumorigenesis were evaluated in vitro and in vivo. Kaplan-Meier curves and the log-rank test were used to analyze disease-free survival and overall survival.Results: TSCC patients with high expression levels of MTHFD1L had shorter overall survival (P < 0.05) and disease-free survival (P < 0.05). Knockdown of MTHFD1L reduced nicotinamide adenine dinucleotide phosphate (NADPH) levels and increased reactive oxygen species (ROS), which accelerated cell death under oxidative stress, such as hypoxia or glucose deprivation. Additionally, inhibition of MTHFD1L suppressed TSCC cell growth and delayed the cell cycle, including in xenograft experiments.Conclusions: MTHFD1L confers redox homeostasis and promotes TSCC cell growth, which provides a great opportunity to study tumor metabolism in head and neck cancer. The mTORC1-4EBP1-eIF4E axis may affect the expression of MTHFD1L in TSCC. Inhibition of the expression of MTHFD1L may be an actionable and effective therapeutic target in TSCC.
Highlights
As a subset of oral cancer, tongue squamous cell carcinoma (TSCC) constitutes more than half of oral SCCs in China and is characterized by its high incidence and poor prognosis [1,2,3]
A Pyeon Multicancer study on the Oncomine database demonstrated that the methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) expression level was 4.50 times higher in TSCC tissues (15 samples) than in normal head and neck tissues (14 samples) and in cervix and uteri tissue (8 samples) (Figure 1A) [18]
We analyzed the levels of MTHFD1L mRNA and protein expression separately in TSCC tissues (T) and adjacent non-carcinoma tissues (ANTs)
Summary
As a subset of oral cancer, tongue squamous cell carcinoma (TSCC) constitutes more than half of oral SCCs in China and is characterized by its high incidence and poor prognosis [1,2,3]. Changes in cell metabolism are known to drive tumor development. Numerous studies have confirmed that metabolic reprogramming occurs in tumorigenesis and in development [4, 5]. Our recent studies investigated the roles of metabolic reprogramming in promoting glycolysis and redox hemostasis [6,7,8]; the regulation of NADP metabolism in TSCC remains unclear and is of interest. Routine changes in cell metabolism can drive tumor development, as the cellular program develops to promote glycolysis and redox homeostasis during tumor progression; the associated mechanisms in tongue squamous cell carcinoma (TSCC) remain unclear
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