Journal
PLOS ONE
Volume 11, Issue 8, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0161009
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Funding
- Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) [14089014]
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- JSPS KAKENHI [14J05219, 15K15751, 23390469]
- Industrial Technology Research Grant Program of the New Energy and the Industrial Technology Development Organization of Japan [P00041]
- Cabinet Office, Government of Japan [LS005]
- Third-Term Comprehensive Control Research for Cancer, Research on Biological Markers for New Drug Development and Health Labour Sciences Research
- Applied Research for Innovative Treatment of Cancer grant by the Ministry of Health, Labour and Welfare of Japan
- Practical Research for Innovation Cancer Control [15ck0106101h0002]
- AMED-CREST by Japan Agency for Medical Research and Development [10801082]
- Grants-in-Aid for Scientific Research [23390469, 14J05219, 15H04913, 15K15751] Funding Source: KAKEN
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Pancreatic cancer is one of the most lethal tumors, and reliable detection of early-stage pancreatic cancer and risk diseases for pancreatic cancer is essential to improve the prognosis. As 260 genes were previously reported to be upregulated in invasive ductal adenocarcinoma of pancreas (IDACP) cells, quantification of the corresponding proteins in plasma might be useful for IDACP diagnosis. Therefore, the purpose of the present study was to identify plasma biomarkers for early detection of IDACP by using two proteomics strategies: antibody-based proteomics and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics. Among the 260 genes, we focused on 130 encoded proteins with known function for which antibodies were available. Twenty-three proteins showed values of the area under the curve (AUC) of more than 0.8 in receiver operating characteristic (ROC) analysis of reverse-phase protein array (RPPA) data of IDACP patients compared with healthy controls, and these proteins were selected as biomarker candidates. We then used our high-throughput selected reaction monitoring or multiple reaction monitoring (SRM/MRM) methodology, together with an automated sample preparation system, micro LC and auto analysis system, to quantify these candidate proteins in plasma from healthy controls and IDACP patients on a large scale. The results revealed that insulin-like growth factor- binding protein (IGFBP) 2 and IGFBP3 have the ability to discriminate IDACP patients at an early stage from healthy controls, and IGFBP2 appeared to be increased in risk diseases of pancreatic malignancy, such as intraductal papillary mucinous neoplasms (IPMNs). Furthermore, diagnosis of IDACP using the combination of carbohydrate antigen 19-9 (CA19-9), IGFBP2 and IGFBP3 is significantly more effective than CA19-9 alone. This suggests that IGFBP2 and IGFBP3 may serve as compensatory biomarkers for CA19-9. Early diagnosis with this marker combination may improve the prognosis of IDACP patients.
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