GC-MS-based metabolomic analysis of human papillary thyroid carcinoma tissue

Abstract

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Elucidating the molecular network that is altered in PTC may lead to the identification of the critical insight into the pathogenesis of PTC. Thus far, little is known regarding the global metabolomic alterations of PTC. Gas chromatography coupled with mass spectrometry-based metabolomics was used to analyze metabolomic alterations in matched PTC and normal thyroid tissues obtained from the patients. Multivariate statistical analyses were employed to determine the significant metabolomic differences. The mRNA levels of the associated metabolic enzyme genes were further assayed with reverse transcription-quantitative polymerase chain reaction analysis. Principal component analysis, partial least-squares discriminant analysis (PLS-DA) and orthogonal PLS-DA models were established, which could clearly separate human normal thyroid and PTC samples, and identified that metabolites in carbohydrate metabolism, including glucose, fructose, galactose, mannose, 2-keto-D-gluconic acid and rhamnose, consistently decreased, while metabolites in nucleotide metabolism, including malonic acid and inosine, and lipid metabolism, including cholesterol and arachidonic acid, significantly altered in PTC. Furthermore, the mRNA levels of metabolic enzyme genes, including glucose-6-phosphate dehydrogenase, phosphoglycerate kinase 1, lactate dehydrogenase A, phosphoglycerate dehydrogenase and prostaglandin-endoperoxide synthase 2, significantly increased in PTC. Based on the metabolomic and mRNA data, various metabolites may be used for increased synthesis of nucleotides and oncogenic lipids in PTC, which may contribute to the pathogenesis of PTC. The present study provides a new understanding of the dysregulated metabolism in PTC and identifies potential avenues for the therapeutic intervention for this disease.

Emerging Role of the Pentose Phosphate Pathway in Hepatocellular Carcinoma

“…Moreover, enhancement of G6PD activity during cell cycle progression, in particular S/G2 phases, was also reported in the human colon cancer cell line HT29 (38). Upregulation of G6PD levels was described in papillary thyroid carcinoma (PTC) (39) and renal cell cancer (40). On the other hand, a very weak G6PD activity was observed in lung cancer (33), and variable results were obtained in breast carcinoma cells (41, 42).…”

A distinct serum metabolic signature of distant metastatic papillary thyroid carcinoma

“…Metabolomics has been extensively employed in cancer research, and plenty metabolic alterations are found in various types of cancers . Results from several recent works demonstrated that metabolomics techniques could help to discriminate different types of thyroid lesions for differential diagnosis, provide significant information about disease progression and unveil potential targets for therapy . However, most of the previous studies used tissue samples except one used serum, one used plasma and one used urine .…”

Metabolic Alterations of Thyroid Cancer as Potential Therapeutic Targets

“…Overexpression of HIF-1 α has been also associated with distant metastasis in PTC [ 24 , 25 ]. Furthermore, HIF-1 α activates the expression of glycolytic enzymes such as the hexokinase II (HKII), phosphoglycerate kinase (PGK), glucose-6-phosphate dehydrogenase (G6PDH), and lactate dehydrogenase A (LDH-A), or glucose and lactate transporters, such as glucose transporter 1 (GLUT1) and the monocarboxylate transporter 4 (MCT4), that have been found overexpressed in TC [ 26 – 29 ]. Overall, these findings suggest that some cells within thyroid tumors rely on aerobic glycolysis for energy production, thus exhibiting the Warburg phenotype.…”

“…Lactate is also a potent signaling molecule involved in angiogenesis [ 74 , 75 ]. Interestingly, when compared with healthy tissues, TC shows increased expression levels and activation of LDH-A, the key enzyme of lactate production in cells [ 26 , 58 ].…”