Post-translational modification by tyrosine sulfation is considered to be a signal for protein secretion and a regulatory mechanism for physiological activity of proteins. We have long studied the enzyme tyrosylprotein sulfotransferase, which is involved in protein tyrosine sulfation, and have elucidated its three-dimensional structure and obtained new knowledge on the substrate protein recognition mechanism. We were involved in the “Creation of Cancer Prevention Basic Technology Focusing on Food Function” and established an innovative technology for evaluating food functionality by combining biomarker search and quantification using proteomics and functionality estimation using informatics such as neural network analysis as a new food function evaluation technology. Furthermore, focusing on the relationship between protein modification and food function, and inspired by the idea of evaluating the antioxidant effect of food using the oxidative stress level of proteins as an indicator, we developed a method for analyzing protein modifications related to oxidative stress, such as protein carbonylation and S-nitrosylation. We also contributed to the proteome analysis and component analysis of local foodstuffs such as pork, sturgeon, and jidori chicken.

Pancreatic cancer is a refractory cancer. The development of a blood biomarker that can detect operable pancreatic cancer and its risk population will lead to the development of an efficient pancreatic cancer screening method, which may reduce mortality. We comprehensively screened circulating peptides in the blood of pancreatic cancer patients and their risk populations, those with benign related diseases, and healthy subjects, and found that the C-terminal amino acids of apolipoprotein-A2 dimers are specifically truncated in pancreatic cancer and in risk populations (apolipoprotein-A2 isoforms, apoA2-i). To apply this finding to clinical practice, we have constructed an enzyme-linked immuno-sorbent assay (ELISA) test system for quantitative analysis of the cleavage state of apoA2-i, and it is now under clinical development.

Clinical performance studies are required to obtain approval for in vitro diagnostics (IVD), and clinical performance studies will be conducted after protocol consultation with the Pharmaceuticals and Medical Devices Agency (PMDA). We established the “Platform for Evaluation of Biomarkers for Cancer Early Detection (P-EBED)” for social implementation of biomarkers that contribute to the early detection of cancer, and initiated verification of the clinical performance of biomarker seeds and support for IVD applications. P-EBED has begun supporting validation of the clinical performance of biomarker seeds and IVD applications.

Many membrane proteins undergo a proteolysis referred to as ectodomain shedding (shedding), by which their extracellular regions are released. Shedding is strictly regulated by signal transduction and other factors, and proteomics is a powerful approach to understand which substrates undergo shedding under specific conditions. In this review, we introduce three proteomics technologies useful for shedding studies: 1) a method for analyzing secreted proteins, based on the fact that many membrane proteins are glycosylated; 2) a method for specifically labeling and analyzing the N-termini of proteins on the cell surface; and 3) a highly sensitive method to isolate protein N- and C-terminal peptides currently developed by our group.

Imaging techniques to distinguish cellular changes are required to elucidate disease mechanisms and to advance diagnosis and treatment. Mass spectrometry imaging, which visualizes the distribution of molecules in biological tissues, is useful for capturing changes of local chemical states of cellular networks containing multiple molecules. In this paper, the development of advanced techniques for measuring spatial distribution information of lipids and proteins at the cellular scale and their application to the imaging of biological tissues will be outlined. Developments of ionization methods for highly sensitive measurement of microdomain components and sample pretreatment methods have expanded the number of molecular species that can be measured. Information on the distribution of molecules involved in the heterogeneity of disease tissues, which cannot be obtained by omics measurement using liquid chromatography-mass spectrometry, will contribute to the development of life science research. Further efforts are demanded to promote the interdisciplinary research and development involving fundamental technologies such as ionization, pretreatment, mass spectrometry, and data analysis, as well as research on actual samples by utilizing these technologies.