Integrated analysis of fine-needle-aspiration cystic fluid proteome, cancer cell secretome, and public transcriptome datasets for papillary thyroid cancer biomarker discovery
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Chia-Chun Wu1,*, Jen-Der Lin4,*, Jeng-Ting Chen7, Chih-Min Chang1, Hsiao-Fen Weng4, Chuen Hsueh5, Hui-Ping Chien5 and Jau-Song Yu1,2,3,6
1Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
2Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
3Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
4Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
5Department of Pathology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
6Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
7Department of Surgery, Department of Medical Research and Development Linkou Branch, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
*These authors contributed equally to this work
Jau-Song Yu, email: [email protected]
Keywords: papillary thyroid carcinoma; fine needle aspiration cystic fluid; proteome profiles; secretome; biomarker
Received: April 20, 2017 Accepted: November 15, 2017 Published: January 04, 2018
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.
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