Abstract
Thyroid ultrasound and ultrasound-guided fine-needle aspiration (USG/FNA) biopsy are currently used for diagnosing papillary thyroid carcinoma (PTC), but their detection limit could be improved by combining other biomarkers. To discover novel PTC biomarkers, we herein applied a GeLC-MS/MS strategy to analyze the proteome profiles of serum-abundant-protein-depleted FNA cystic fluid from benign and PTC patients, as well as two PTC cell line secretomes. From them, we identified 346, 488, and 2105 proteins, respectively. Comparative analysis revealed that 191 proteins were detected in the PTC but not the benign cystic fluid samples, and thus may represent potential PTC biomarkers. Among these proteins, 101 were detected in the PTC cell line secretomes, and seven of them (NPC2, CTSC, AGRN, GPNMB, DPP4, ERAP2, and SH3BGRL3) were reported in public PTC transcriptome datasets as having 4681 elevated mRNA expression in PTC. Immunoblot analysis confirmed the elevated expression levels of five proteins (NPC2, CTSC, GPNMB, DPP4, and ERAP2) in PTC versus benign cystic fluids. Immunohistochemical studies from near 100 pairs of PTC tissue and their adjacent non-tumor counterparts further showed that AGRN (n = 98), CTSC (n = 99), ERAP2 (n = 98) and GPNMB (n = 100) were significantly (p < 0.05) overexpressed in PTC and higher expression levels of AGRN and CTSC were also significantly associated with metastasis and poor prognosis of PTC patients. Collectively, our results indicate that an integrated analysis of FNA cystic fluid proteome, cancer cell secretome and tissue transcriptome datasets represents a useful strategy for efficiently discovering novel PTC biomarker candidates.
Highlights
Thyroid cancer is the most prevalent malignant endocrine carcinoma in the world
Immunohistochemical studies from near 100 pairs of papillary thyroid carcinoma (PTC) tissue and their adjacent non-tumor counterparts further showed that AGRN (n = 98), CTSC (n = 99), endoplasmic reticulum aminopeptidase 2 (ERAP2) (n = 98) and glycoprotein NMB (GPNMB) (n = 100) were significantly (p < 0.05) overexpressed in PTC and higher expression levels of AGRN and CTSC were significantly associated with metastasis and poor prognosis of PTC patients
Our results indicate that an integrated analysis of FNA cystic fluid proteome, cancer cell secretome and tissue transcriptome datasets represents a useful strategy for efficiently discovering novel PTC biomarker candidates
Summary
Thyroid cancer is the most prevalent malignant endocrine carcinoma in the world. Preoperative ultrasoundguided fine-needle aspiration (USG/FNA) followed by cytopathologic diagnosis is the standard procedure for examining thyroid nodules and determining therapeutic modalities [3]. 10–20% yield indeterminate biopsy results on preoperative USG/FNA diagnosis. These patients normally undergo thyroidectomy, but this is often unnecessary, as postsurgery immunohistological analysis has shown that 80% of the suspicious cases are benign [4, 5]. If we hope to reduce unnecessary thyroidectomies and prevent deterioration in PTC, we urgently need reliable biomarkers that can distinguish between benign and malignant nodules in patients with indeterminate lesions
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