Metabolomics is considered an effective method to identify diagnostic biomarkers and a tool to better understand the mechanism of diseases. During the past two decades, some previous studies have investigated the metabolic perturbations between healthy and thyroid nodules using serum, tissue and urine samples with advanced detection techniques such as gas chromatography–mass spectrometry (GC–MS) [17-19], liquid chromatography–mass spectrometry (LC–MS) [20], and proton nuclear magnetic resonance (1H-NMR) [21]. However, to our knowledge, this is the first report to explore the metabolic mechanisms of thyroid cancer in different backgrounds.
We identified the metabolic profiles of NC and HT using the UPLC-Q-TOF/MS approach, which demonstrated some similarities and differences in metabolic pathways. These two groups have common metabolic pathways, such as taurine and hypo-taurine metabolism, arginine biosynthesis, alanine, aspartate and glutamate metabolism, arginine and proline metabolism and D-glutamine and D-glutamate metabolism. Based on the metabolite enrichment analysis results, D-glutamine and D-glutamate metabolism and taurine and hypo-taurine metabolism were regarded as important factors influencing PTC development by affecting energy metabolism, which is consistent with other studies [22-24]. Based on the metabolic pathway of thyroid papillary carcinoma under different backgrounds, this study more comprehensively reflects the metabolic differences between thyroid cancer tissue and paracancerous tissue, making up for the shortcomings of previous studies.
Glutamine is a compound essential for tumor growth, as a nonessential amino acid, plays an important role directly or indirectly in tumorigenesis and cancer cell survival [25].Torregrossa et al. [26]used 1H-HRMAS NMR spectroscopy to find metabolic changes in benign nodular goiter, malignant (PTC, FTC, and ATC) nodules, and normal thyroid tissue, and the results showed glutamate levels were increased in tumor samples. Yu et al. [27]studied four PTC cell lines (K1, IHH4, BCPAP, and TPC-1) and tissue samples using several molecular and biochemical approaches revealing that glutamate was overexpressed in cancer specimens and played a prominent role in the development and progression of PTC. Based on the results, the D-glutamine and D-glutamate pathways could be regarded as potential targets for PTC therapy. Furthermore, a previous study had reported the association between thyroid autoimmunity and PTC, and the increased serum glutamine levels might be involved [22]. All these results require further investigation.
Another finding of this study is that there may be a significant increase in taurine content in PTC tissues, and the change in taurine may lead to changes in taurine and hypo-taurine metabolism pathways. Similarly, in Torregrossa et al.’s [26]study increased levels of metabolites such as lactic acid and taurine were found to be characteristic of malignant tumors. Another metabolomic study on thyroid nodules found that compared with benign nodules, the contents of lactic acid and taurine were increased in malignant thyroid nodules [23,28].Taurine is believed to have antioxidant properties and has been implicated in the treatment of neurodegenerative disease, atherosclerosis, coronary heart disease, and prostate cancer [29,30]. In some previous studies, it has been found that taurine can inhibit tumor cell proliferation, enhance apoptosis, and inhibit angiogenesis and play an anti-tumor role[31]. Hence, it will be essential to unravel the biological mechanism underlying taurine and hypo-taurine metabolism and then to find the effect of other factors on it in thyroid cancer.
The link between HT and PTC has been focus of controversy [32-34]. In our study, PTC tissues and adjacent tissues in the HT background also had specific metabolic pathways compared with the normal background group, including aminoacyl-tRNA biosynthesis, glycine, serine and threonine metabolism [35]. Li et al. [36] found significant alterations in the aminoacyl-tRNA biosynthesis pathway in their metabolomic study of PTC and suggested that abnormalities in this pathway were related to abnormal protein synthesis in PTC. The contents of arginine and serine involved in the aminoacyl tRNA biosynthesis pathway may be significantly elevated in PTC tissues in the context of HT [35,37]. Consistent with Liu et al’s study [38], glycine and l-serine levels were reduced in patients with autoimmune thyroid disease. It is worth noting that Sun et al. [37]indicated that the expression rate of serine/glycine metabolism-related proteins was higher in PTC cases with the BRAF V600E mutation. As is known, PTC with a BRAF V600E has mutation have more aggressive tumor biology. Whether PTC has a better prognosis in the context of HT is related to this should be further explored.
The metabolism of PTC is complex. We identified arginine, glutamic acid, cysteine, citric acid, malic acid, uracil and taurine as combined biomarkers for PTC diagnosis. These seven metabolites were defined as a combinatorial biomarker to assist needle biopsy for PTC diagnosis as demonstrated by ROC analysis, which revealed an AUC values of 0.867 and 0.973. Therefore, the potential combinatorial biomarkers provide a new direction for exploring auxiliary methods for PTC diagnosis, although a large number of samples is needed to confirm this diagnostic mode.
This study has limitations. First, we had only a small sample of patients who fulfilled our inclusion criteria. Further large-scale prospective studies are needed. Second, these potential metabolic biomarkers need to be verified in the future large-scale populations.