Tumour metabolomics and transcriptomics co-expression network as related to biological folate alteration and cancer malignancy remains unexplored in human non-small cell lung cancers (NSCLC). To probe the diagnostic biomarkers, tumour and pair lung tissue samples (n = 56) from 97 NSCLC patients were profiled for ultra-performance liquid chromatography tandem mass spectrometry (UPLC/MS/MS)-analysed metabolomics, targeted transcriptionomics, and clinical folate traits. Weighted Gene Co-expression Network Analysis (WGCNA) was performed. Tumour lactate was identified as the top VIP marker to predict advance NSCLC (AUC = 0.765, Sig = 0.017, CI 0.58–0.95). Low folate (LF)-tumours vs. adjacent lungs displayed higher glycolytic index of lactate and glutamine-associated amino acids in enriched biological pathways of amino sugar and glutathione metabolism specific to advance NSCLCs. WGCNA classified the green module for hub serine-navigated glutamine metabolites inversely associated with tumour and RBC folate, which module metabolites co-expressed with a predominant up-regulation of LF-responsive metabolic genes in glucose transport (GLUT1), de no serine synthesis (PHGDH, PSPH, and PSAT1), folate cycle (SHMT1/2 and PCFR), and down-regulation in glutaminolysis (SLC1A5, SLC7A5, GLS, and GLUD1). The LF-responsive WGCNA markers predicted poor survival rates in lung cancer patients, which could aid in optimizing folate intervention for better prognosis of NSCLCs susceptible to folate malnutrition.
Objectives Lung cancer patients may suffer from one-carbon malnutrition due to insufficient dietary intake or one-carbon enzymes genotypic diversity. However, the correlation of one-carbon metabolites and lung cancer risk, malignant progression is still unclear. Our objective was to examine methyl donor status and tumor stages. Methods The cross-sectional recruited 32 non-small cell lung cancer (NSCLC) patients in National Taiwan University Hospital (NTUH), Taiwan. Nutrition, clinical pathological and biochemical data were collected. Long-term nutritional intake was evaluated by one-carbon semi-quantitative dietary frequency questionnaire, biochemical values were analyzed by Liquid chromatography–mass spectrometry (LC/MS), Tumor information was collected by department of pathology in NTUH. Results Data revealed that marginal deficiency rate of dietary folate intake was 26.4%, over UL value (>1000mcg) was 9.4%. Energy adjusted folate, free-choline and betaine intake had significantly positive correlation (r = 0.519, r = 0.336, r = 0.388, P < 0.05); Energy adjusted folate and vitamin B12 intake had positive correlation (r = 0.184). According to TNM stages, we classified NSCLC tumor stages and found that increasing energy adjusted folate intake was significantly positive correlated with late stage (P = .001). The adjusted dietary folate in late stages was significantly higher than early stage (P < 0.05). The clinical value of plasma marginal folate deficiency rate was 12.5%, plasma marginal high of homocysteine rate was 15.6%. Plasma free-choline and betaine levels had significantly positive correlation (r = 0.495, P = 0.023). Otherwise, plasma folate and betaine, free-choline levels had negative correlation (r = −0.166, r = −0.075), and plasma folate levels had positive correlation with vitamin B12 (r = 0.353). The plasma folate levels had significantly positive correlation with energy adjusted folate intake (r = 0.464, P = 0.034). Increasing plasma folate level was positive correlated with late tumor stage (r = 0.108). Conclusions In summary, higher one-carbon nutrients intake status may be associated with tumor lymphatic metastasis stages of NSCLC patients. Funding Sources Ministry of Science and Technology.
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