Abstract
The aim of the present study was to identify time-dependent changes in the expression of metabolic biomarkers during the various stages of oral carcinogenesis to provide an insight into the sequential mechanism of oral cancer development. An 1H nuclear magnetic resonance (NMR)-based metabolomics approach was used to analyze the blood plasma samples of Sprague-Dawley rats exhibiting various oral lesions induced by the administration of 4-nitroquinoline-1-oxide (4NQO) in drinking water. The 1H NMR spectra were processed by principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) to determine the metabolic differences between the three developmental stages of oral mucosa cancer (health, oral leukoplakia [OLK] and oral squamous cell carcinoma [OSCC]). The variable importance in projection (VIP) score derived from the PLS-DA model was used to screen for important metabolites, whose significance was further verified through analysis of variance (ANOVA). Data from the present study indicated that 4NQO-induced rat oral carcinogenesis produced oral pre-neoplastic and neoplastic lesions and provided an effective model for analyzing sequential changes in the 1H NMR spectra of rat blood plasma. The 1H NMR-based metabolomics approach clearly differentiates between healthy, OLK and OSSC rats in the PCA and PLS-DA models. Furthermore, lactic acid, choline, glucose, proline, valine, isoleucine, aspartic acid and 2-hydroxybutyric acid demonstrated VIP>1 in the PLS-D model and P<0.05 with ANOVA. It was also identified that increases in lactic acid, choline and glucose, and decreases in proline, valine, isoleucine, aspartic acid and 2-hydroxybutyric acid may be relative to the characteristic mechanisms of oral carcinogenesis. Therefore, these plasma metabolites may serve as metabolic biomarkers in oral carcinogenesis and assist in the early diagnosis and preventive treatment of oral cancer.
Highlights
Advanced‐stage oral cancer is associated with high incidences of mortality, morbidity and disfigurement worldwide
The data from the present study indicates that 1H nuclear magnetic resonance (NMR)‐based metabolomic analyses of plasma distinguish between OSCC, OLK and healthy rats
Using the rat model, significant increases in lactic acid, choline, and glucose (P
Summary
Advanced‐stage oral cancer is associated with high incidences of mortality, morbidity and disfigurement worldwide. It is important that oral cancer is detected early for improved prevention, prognosis and treatment [1]. A number of novel techniques have been developed that aid with the early detection of oral cancer [2], for example metabolomics assesses and validates metabolite concentrations within cells, tissues and biofluid. Metabolomic analyses of the biofluid of oral cancer patients (such as urine, serum and saliva) have been performed using differential measurement techniques, including nuclear magnetic resonance (NMR), high performance liquid chromatography‐mass spectrometry (HPLC‐MS) and gas chromatography (GC)‐MS. Previous studies, including our previous study [3,4,5,6,7] have analyzed human biofluid to demonstrate the applicability of metabolomics in the diagnosis and prognosis of oral cancer. Difficulty identifying the metabolic markers of oral cancer and metabolic differences between the stages of oral carcinogenesis (healthy, oral leukoplakia [OLK] and oral squamous cell carcinoma [OSCC]) may be due to variations in the above‐mentioned human variables
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