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Serum fucosylated receptor expression‑enhancing protein 5 as a biomarker for early stage pancreatic cancer

  • Authors:
    • Kazuyuki Sogawa
    • Riko Yonekubo
    • Momori Shimizu
    • Satoshi Muraoka
    • Jun Adachi
    • Shigetsugu Takano
    • Hirotaka Takizawa
    • Masayuki Ohtsuka
    • Takeshi Tomonaga
  • View Affiliations / Copyright

    Affiliations: Department of Molecular Diagnosis, Graduate School of Environmental Health, Azabu University, Sagamihara, Kanagawa 252‑5201, Japan, Department of Biochemistry, School of Life and Environmental Science, Azabu University, Sagamihara, Kanagawa 252‑5201, Japan, Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567‑0085, Japan, Department of General Surgery, Graduate School of Medicine, Chiba University, Chuo, Chiba 260‑8677, Japan, Kashiwado Clinic in Port‑Square, Kashiwado Memorial Foundation, Chuo, Chiba 260‑0025, Japan
    Copyright: © Sogawa et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 556
    |
    Published online on: September 26, 2025
       https://doi.org/10.3892/ol.2025.15302
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and is a leading cause of cancer mortality. Early diagnosis is difficult due to the anatomical characteristics of the pancreas, which is a long and thin organ located dorsal to the stomach and large intestine. The aim of the present study was to search for protein biomarkers for PDAC in serum extracellular vesicles (EVs) using mass spectrometry, and to validate identified biomarkers using an enzyme‑linked immunosorbent assay (ELISA) of sera from patients. Comprehensive and targeted proteomic analyses for biomarker discovery and verification were performed using EVs from serum of patients with PDAC, patients with chronic pancreatitis (PT) and healthy volunteers (HVs). For validation, the discriminatory power of candidate proteins was evaluated using an ELISA. Of the 3,043 proteins analyzed, 45 were identified as potential biomarkers, with receptor expression‑enhancing protein 5 (REEP5) selected for further analysis. The serum level of fucosylated REEP5 was significantly higher in PDAC cases compared with in PT and HVs (P<0.001). The areas under the curve (AUC) of the receiver operator characteristic were 0.928 for fucosylated REEP5 and 0.805 for carbohydrate antigen 19‑9 (CA19‑9) in PDAC vs. non‑cancer controls. The AUCs were 0.962 for fucosylated REEP5 and 0.810 for CA19‑9 in stages I and II of PDAC. These results indicate that fucosylated REEP5 is a novel serum EV biomarker for detection of early stage PDAC. Further analysis in a larger cohort is warranted to evaluate the clinical utility of fucosylated REEP5 as a biomarker for PDAC.
View Figures

Figure 1

PDAC biomarker discovery in EVs.
Overview of biomarker candidate selection, showing the selection
method at each step and the number of remaining candidate proteins.
EVs, extracellular vesicles; HVs, healthy volunteers; PT, chronic
pancreatitis; PDAC, pancreatic ductal adenocarcinoma; DIA,
data-independent acquisition; SRM, selected reaction
monitoring.

Figure 2

Verification of biomarker candidate
proteins using targeted proteomics. The two REEP5 peptides with
highest intensity (A) ETADAITK and (B) ATVNLLGEEK were selected.
Relative quantitation of peptides of biomarker candidates was
performed using selected reaction monitoring analysis. HVs, healthy
volunteers; PT, chronic pancreatitis; PDAC, pancreatic ductal
adenocarcinoma; REEP5, receptor expression-enhancing protein 5.

Figure 3

REEP5 protein is detected in total
serum. Representative western blot of REEP5 and albumin in total
serum (5.0 µg protein loaded per column) of patients with PDAC and
HVs. REEP5, receptor expression-enhancing protein 5; HVs, healthy
volunteers; PDAC, pancreatic ductal adenocarcinoma.

Figure 4

REEP5 and fucosylated REEP5 levels in
HVs and in PT and PDAC. (A) Serum REEP5 levels in the third cohort
were 0.16±0.04, 0.16±0.03 and 0.21±0.12 ng/ml in HVs, PT and PDAC,
respectively. (B) Serum fucosylated REEP5 levels in the third
cohort were 0.03±0.01, 0.03±0.01 and 0.12±0.10 AU/ml in HVs, PT and
PDAC, respectively. HVs, healthy volunteers; PT, chronic
pancreatitis; PDAC, pancreatic ductal adenocarcinoma; REEP5,
receptor expression-enhancing protein 5.

Figure 5

Fucosylated REEP5, CA19-9 and CEA
levels in HVs and patients with chronic pancreatitis and PDAC
(stage I–IV). (A) Serum fucosylated REEP5, (B) serum CA19-9 and (C)
serum CEA levels in the third cohort. REEP5, receptor
expression-enhancing protein 5; CA19-9, carbohydrate antigen 19-9;
CEA, carcinoembryonic antigen; HVs, healthy volunteers; PDAC,
pancreatic ductal adenocarcinoma.

Figure 6

Fucosylated REEP5 is superior to
CA19-9 for early detection of PDAC. (A) AUCs were 0.928 for
fucosylated REEP5 and 0.805 for CA19-9 for distinguishing cancer
(PDAC) from non-cancer (healthy volunteers and chronic
pancreatitis) cases. (B) AUCs for distinguishing PDAC from
non-cancer cases were 0.962 for fucosylated REEP5 and 0.810 for
CA19-9. (C) AUCs for distinguishing PDAC (stage I and II) from
non-cancer cases were 0.857 for fucosylated REEP5 combined with
CEA, and 0.999 for fucosylated REEP5 combined with CA19-9. REEP5,
receptor expression-enhancing protein 5; CA19-9, carbohydrate
antigen 19-9; PDAC, pancreatic ductal adenocarcinoma; CEA,
carcinoembryonic antigen; AUC, area under the curve.
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Copy and paste a formatted citation
Spandidos Publications style
Sogawa K, Yonekubo R, Shimizu M, Muraoka S, Adachi J, Takano S, Takizawa H, Ohtsuka M and Tomonaga T: Serum fucosylated receptor expression‑enhancing protein 5 as a biomarker for early stage pancreatic cancer. Oncol Lett 30: 556, 2025.
APA
Sogawa, K., Yonekubo, R., Shimizu, M., Muraoka, S., Adachi, J., Takano, S. ... Tomonaga, T. (2025). Serum fucosylated receptor expression‑enhancing protein 5 as a biomarker for early stage pancreatic cancer. Oncology Letters, 30, 556. https://doi.org/10.3892/ol.2025.15302
MLA
Sogawa, K., Yonekubo, R., Shimizu, M., Muraoka, S., Adachi, J., Takano, S., Takizawa, H., Ohtsuka, M., Tomonaga, T."Serum fucosylated receptor expression‑enhancing protein 5 as a biomarker for early stage pancreatic cancer". Oncology Letters 30.6 (2025): 556.
Chicago
Sogawa, K., Yonekubo, R., Shimizu, M., Muraoka, S., Adachi, J., Takano, S., Takizawa, H., Ohtsuka, M., Tomonaga, T."Serum fucosylated receptor expression‑enhancing protein 5 as a biomarker for early stage pancreatic cancer". Oncology Letters 30, no. 6 (2025): 556. https://doi.org/10.3892/ol.2025.15302
Copy and paste a formatted citation
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Spandidos Publications style
Sogawa K, Yonekubo R, Shimizu M, Muraoka S, Adachi J, Takano S, Takizawa H, Ohtsuka M and Tomonaga T: Serum fucosylated receptor expression‑enhancing protein 5 as a biomarker for early stage pancreatic cancer. Oncol Lett 30: 556, 2025.
APA
Sogawa, K., Yonekubo, R., Shimizu, M., Muraoka, S., Adachi, J., Takano, S. ... Tomonaga, T. (2025). Serum fucosylated receptor expression‑enhancing protein 5 as a biomarker for early stage pancreatic cancer. Oncology Letters, 30, 556. https://doi.org/10.3892/ol.2025.15302
MLA
Sogawa, K., Yonekubo, R., Shimizu, M., Muraoka, S., Adachi, J., Takano, S., Takizawa, H., Ohtsuka, M., Tomonaga, T."Serum fucosylated receptor expression‑enhancing protein 5 as a biomarker for early stage pancreatic cancer". Oncology Letters 30.6 (2025): 556.
Chicago
Sogawa, K., Yonekubo, R., Shimizu, M., Muraoka, S., Adachi, J., Takano, S., Takizawa, H., Ohtsuka, M., Tomonaga, T."Serum fucosylated receptor expression‑enhancing protein 5 as a biomarker for early stage pancreatic cancer". Oncology Letters 30, no. 6 (2025): 556. https://doi.org/10.3892/ol.2025.15302
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