Identification of Fucosylated SERPINA1 as a Novel Plasma Marker for Pancreatic Cancer Using Lectin Affinity Capture Coupled with iTRAQ-Based Quantitative Glycoproteomics.

Chia-Chun Wu,Srinivas Dash,Ta-Sen Yeh,Jau-Song Yu,Yu-Ting Lu,Yun-Hsin Chan

doi:10.3390/ijms22116079

Abstract

Pancreatic cancer (PC) is an aggressive cancer with a high mortality rate, necessitating the development of effective diagnostic, prognostic and predictive biomarkers for disease management. Aberrantly fucosylated proteins in PC are considered a valuable resource of clinically useful biomarkers. The main objective of the present study was to identify novel plasma glycobiomarkers of PC using the iTRAQ quantitative proteomics approach coupled with Aleuria aurantia lectin (AAL)-based glycopeptide enrichment and isotope-coded glycosylation site-specific tagging, with a view to analyzing the glycoproteome profiles of plasma samples from patients with non-metastatic and metastatic PC and gallstones (GS). As a result, 22 glycopeptides with significantly elevated levels in plasma samples of PC were identified. Fucosylated SERPINA1 (fuco-SERPINA1) was selected for further validation in 121 plasma samples (50 GS and 71 PC) using an AAL-based reverse lectin ELISA technique developed in-house. Our analyses revealed significantly higher plasma levels of fuco-SERPINA1 in PC than GS subjects (310.7 ng/mL v.s. 153.6 ng/mL, p = 0.0114). Elevated fuco-SERPINA1 levels were associated with higher TNM stage (p = 0.024) and poorer prognosis for overall survival (log-rank test, p = 0.0083). The increased plasma fuco-SERPINA1 levels support the utility of this protein as a novel prognosticator for PC.

Highlights

Pancreatic cancer (PC) is the most lethal malignant disease associated with a high mortality rate
Plasma samples were collected from all subjects for measurement of proteins and glycoproteins
Our results suggest that plasma levels of both fuco-SERPINA1 and SERPINA1 protein may serve as effective novel prognosticators of PC

Summary

Introduction

Pancreatic cancer (PC) is the most lethal malignant disease associated with a high mortality rate. The 5-year survival rates of PC are reported as ~8% and 9% in the United. In 2016, PC was ranked the eighth leading cause of cancer-related mortality in Taiwan. Since the majority of early-stage (stage I or II). PC cases are asymptomatic, ~80% patients present at later stages (stage III or IV) of disease progression with metastatic spread and unresectable tumors at the time of diagnosis [3,4]. For patients with locally resectable non-metastatic disease, surgical resection followed by adjuvant chemotherapy is the main treatment modality. Chemotherapy administered to patients with advanced disease is frequently associated with treatment resistance and unfavorable side effects. Effective management of PC remains a major challenge [5]

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