Abstract
BackgroundThe aim of this study was to investigate the expression and clinical implications of proteins related to serine/glycine metabolism in different subtypes of thyroid cancer.MethodsTissue microarray (TMA) was constructed with tissues from 557 thyroid cancers, consisting of 244 papillary thyroid carcinomas (PTC), 112 follicular carcinomas (FC), 70 medullary carcinomas (MC), 23 poorly differentiated carcinomas (PDC), and 8 anaplastic carcinomas (AC). Immunohistochemical staining of the serine/glycine metabolism-related molecules phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase, (PSAT), phosphoserine phosphatase (PSPH), serine hydromethyl transferase (SHMT), and glycine decarboxylase (GLDC) was performed with the TMA blocks and the results were analyzed together with clinicopathologic parameters.ResultsThe expression of serine/glycine metabolism-related proteins differed among thyroid cancer subtypes. The expression rate of PHGDH (p < 0.001), PSAT1 (p = 0.001), PSPH (p = 0.008), and tumoral SHMT1 (p < 0.001) was higher in PDC and PTC (78.3, 21.7, 21.7, 30.4 and 63.4, 18.6, 12.8, 31.4 %, respectively), and lowest in MC (15.7, 1.4, 0.0, 10.0 %). Stromal SHMT1 expression was highest in AC (62.5 %) and absent in all FC (p < 0.001). In PTC, positivity for PSPH (p = 0.041), tumoral SHMT1 (p = 0.018), and stromal SHMT1 (p < 0.001) expression was higher in the conventional type compared to follicular type (14.1 versus 2.5 %, 33.6 versus 15.0 %, 42.1 versus 10.0 %, respectively). BRAF V600E mutation was associated with a higher rate of PHGDH (p < 0.001), PSAT1 (p = 0.001), PSPH (p < 0.001), tumoral SHMT1 (p = 0.001), stromal SHMT1 (p < 0.001), and GLDC (p < 0.001) expression compared to non-mutant cases (73.5 versus 40.6 %, 23.1 versus 8.5 %, 17.6 versus 1.9 %, 37.0 versus 18.9 %, 45.8 versus 21.7 %, 21.8 versus 6.6 %, respectively). In univariate analysis, stromal SHMT1 expression was associated with shorter disease-free survival (p = 0.015) in follicular variant PTC, and GLDC positivity was associated with shorter overall survival (OS) in sclerotic stromal type (p = 0.002). In FC, minimally invasive type, PSPH positivity correlated with shorter OS (p = 0.045) and in MC, PHGDH positivity correlated with shorter OS (p = 0.034).ConclusionThe expression of serine/glycine metabolism-related proteins differs among different thyroid cancer types, with a higher rate of expression in PDC and PTC, and lower rate of expression in MC. In PTC, the rate of expression is lower in the follicular variant and higher in cases with BRAF V600E mutation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0915-8) contains supplementary material, which is available to authorized users.
Highlights
The aim of this study was to investigate the expression and clinical implications of proteins related to serine/glycine metabolism in different subtypes of thyroid cancer
BRAF V600E mutation was associated with a higher rate of phosphoglycerate dehydrogenase (PHGDH) (p < 0.001), PSAT1 (p = 0.001), PSPH (p < 0.001), tumoral SHMT1 (p = 0.001), stromal SHMT1 (p < 0.001), and glycine decarboxylase (GLDC) (p < 0.001) expression compared to non-mutant cases (73.5 versus 40.6 %, 23.1 versus 8.5 %, 17.6 versus 1.9 %, 37.0 versus 18.9 %, 45.8 versus 21.7 %, 21.8 versus 6.6 %, respectively)
Stromal SHMT1 expression was associated with shorter disease-free survival (p = 0.015) in follicular variant papillary thyroid carcinomas (PTC), and GLDC positivity was associated with shorter overall survival (OS) in sclerotic stromal type (p = 0.002)
Summary
The aim of this study was to investigate the expression and clinical implications of proteins related to serine/glycine metabolism in different subtypes of thyroid cancer. Recent studies reported that the metabolism of glycolytic intermediates is involved in tumorigenesis, for example through the glycine and serine metabolic pathways [2,3,4,5]. In the serine biosynthesis pathway, the 3-phosphoglycerate (3PG) that is generated in the glycolysis process is oxidized to 3-phosphohydroxypyruvate (pPYR) by phosphoglycerate dehydrogenase (PHGDH) [6]. Expression of PHGDH was reported to be increased in breast cancer and melanoma [3, 4], and expression of GLDC was reported to be increased in lung cancer [5], revealing a role of proteins related to serine/ glycine metabolism in tumorigenesis
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