Abstract
The incidence of papillary thyroid carcinoma (PTC) is increasing. Lymph node metastatic status of PTC is a major factor for decision marking of surgery and surgical extend, however, no reliable tool exists for prediction of PTC nodal metastasis, for example, ultrasound cannot qualitatively diagnose and effectively detect central lymph node metastasis (CLNM). Therefore, the development of a new diagnostic biomarker is crucial for CLNM. Metabolic dysregulation is an important factor associated with malignancy and metastasis of tumors. Pyruvate carboxylase (PC) is a major anaplerotic enzyme that catalyzes the carboxylation of pyruvate to form oxaloacetate, which has been suggested to be involved in the tumorigenesis of several cancers, including PTC. This study aimed to explore the role of PC expression in thyroid fine-needle aspiration (FNA) wash-out fluid for predicting CLNM in PTC, and to explore how PC is involved in PTC development. The expression levels of PC in PTC tissues and normal thyroid tissues were first compared based on bioinformatics analysis of public databases, including the Gene Expression Profiling (GEPIA), Oncomine and Gene Expression Omnibus (GEO) databases. Then, the PC mRNA and protein expression levels were measured by RT-PCR and Immunohistochemistry (IHC) in surgical tissues from a total of 42 patients with surgically confirmed PTC, and compared in patients with and without CLNM. Further, to assess PC expression in diagnostic biopsies, a total of 71 thyroid nodule patients with ultrasound-guided FNA wash-out fluid samples and cytological diagnosis were prospectively enrolled in the study. Then, we analyzed the mechanism of PC-mediated PTC progression in vitro. This study showed that PC expression was higher in PTC tissues and thyroid FNA wash-out fluid samples from patients with CLNM than those from patients without CLNM, and that PC-induced PTC metastasis may occur through the TGF-β/Smad-regulated epithelial–mesenchymal transition (EMT) pathway.
Highlights
Thyroid carcinoma is the most common endocrine tumor in the world, and its worldwide incidence has significantly increased recently [1, 2]
Pyruvate carboxylase (PC) mRNA expression in the Gene Expression Profiling Interactive Analysis (GEPIA) datasets differed in different types of tumors (Figures 1A, B) but was significantly overexpressed in thyroid cancers (THCAs) (Figures 1C, D)
In Vasko’s dataset, PC was overexpressed in THCA samples versus normal samples with a fold change of 2.516 (Figure 2A)
Summary
Thyroid carcinoma is the most common endocrine tumor in the world, and its worldwide incidence has significantly increased recently [1, 2]. 90% of thyroid cancers (THCAs), including papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), are well differentiated [3]. PTC is the most common subtype, accounting for 80–85% of all malignant thyroid tumors [2]. PTCs exhibit indolent biological behavior [4], and the 5-year survival rate reaches almost 95% after treatment [5], including surgery and radioactive iodine therapy. There is a debate about whether or not PTC, especially papillary thyroid microcarcinoma (PTMC), is overdiagnosed and overtreated. Some PTMCs show nodular enlargement and early lymph node metastasis during the surveillance period [7]. It is critical to develop a tool to identify patients with early nodal metastasis to guide clinical management
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