Abstract
Perturbations in lipid metabolic pathways to meet the bioenergetic and biosynthetic requirements is a principal characteristic of cancer cells. Sphingolipids (SPLs) are the largest class of bioactive lipids associated to various aspects of tumorigenesis and have been extensively studied in cancer cell lines and experimental models. The clinical relevance of SPLs in human malignancies however is still poorly understood and needs further investigation. In the present study, we adopted a UHPLC-High resolution (orbitrap) Mass spectrometry (HRMS) approach to identify various sphingolipid species in breast cancer patients. A total of 49 SPLs falling into 6 subcategories have been identified. Further, integrating the multivariate analysis with metabolomics enabled us to identify an elevation in the levels of ceramide phosphates and sphingosine phosphates in tumor tissues as compared to adjacent normal tissues. The expression of genes involved in the synthesis of reported metabolites was also determined in local as well as TCGA cohort. A significant upregulation in the expression of CERK and SPHK1 was observed in tumor tissues in local and TCGA cohort. Sphingomyelin levels were found to be high in adjacent normal tissues. Consistent with the above findings, expression of SGMS1 in tumor tissues was downregulated in TCGA cohort only. Clinical correlations of the selected metabolites and their performance as biomarkers was also evaluated. Significant ROC and positive correlation with Ki67 index highlight the diagnostic potential and clinical relevance of ceramide phosphates in breast cancer.
Highlights
Perturbations in lipid metabolic pathways to meet the bioenergetic and biosynthetic requirements is a principal characteristic of cancer cells
A comprehensive profiling of SPLs was performed in tumor and adjacent normal tissues obtained from breast cancer patients
partial least square discriminant analysis (PLSDA) is a method used to sharpen the separation among different observation groups and predict the discriminant variable using the Variable Importance in Projection (VIP) scores
Summary
Perturbations in lipid metabolic pathways to meet the bioenergetic and biosynthetic requirements is a principal characteristic of cancer cells. Numerous studies have described the elementary role of ceramide and sphingosine 1-phosphate rheostat in various types of cancers such as lung, breast and colon These studies have provided the mechanistic details of sphingolipid metabolism in cancer cell lines and experimental models[5,6,7], while their role in human malignancies is still poorly understood and needs further elucidation. Though an elevation in the levels of bioactive SPLs has been reported earlier in human breast cancer patient samples[10], a little is known about the use of these metabolites as clinically relevant biomarkers. To validate the role of selected sphingolipid metabolites in breast cancer, we analyzed the expression of genes involved in their synthesis in the local patient cohort as well as TCGA cohort
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