Secretome-Based Identification of ULBP2 as a Novel Serum Marker for Pancreatic Cancer Detection

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Abstract

Background

To discover novel markers for improving the efficacy of pancreatic cancer (PC) diagnosis, the secretome of two PC cell lines (BxPC-3 and MIA PaCa-2) was profiled. UL16 binding protein 2 (ULBP2), one of the proteins identified in the PC cell secretome, was selected for evaluation as a biomarker for PC detection because its mRNA level was also found to be significantly elevated in PC tissues.

Methods

ULBP2 expression in PC tissues from 67 patients was studied by immunohistochemistry. ULBP2 serum levels in 154 PC patients and 142 healthy controls were measured by bead-based immunoassay, and the efficacy of serum ULBP2 for PC detection was compared with the widely used serological PC marker carbohydrate antigen 19-9 (CA 19-9).

Results

Immunohistochemical analyses revealed an elevated expression of ULPB2 in PC tissues compared with adjacent non-cancerous tissues. Meanwhile, the serum levels of ULBP2 among all PC patients (n = 154) and in early-stage cancer patients were significantly higher than those in healthy controls ( p<0.0001). The combination of ULBP2 and CA 19-9 outperformed each marker alone in distinguishing PC patients from healthy individuals. Importantly, an analysis of the area under receiver operating characteristic curves showed that ULBP2 was superior to CA 19-9 in discriminating patients with early-stage PC from healthy controls.

Conclusions

Collectively, our results indicate that ULBP2 may represent a novel and useful serum biomarker for pancreatic cancer primary screening.

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Most cited references 33

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1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience.

Jordan Winter, John L. Cameron, Kurtis A. Campbell … (2006)

Pancreaticoduodenectomy (PD) with the possible addition of neoadjuvant or adjuvant therapy is the standard of care in the United States for adenocarcinoma originating in the pancreatic head, neck, and uncinate process. We reviewed 1423 patients who underwent a PD for a malignancy originating in the pancreas at our institution between 1970 and 2006. We examined 1175 PDs for ductal adenocarcinomas in greater detail. Eighteen different histological types of pancreatic cancer were identified; the most common diagnoses included ductal adenocarcinoma, neuroendocrine carcinoma, and IPMN with invasive cancer. Patients with ductal adenocarcinoma were analyzed in detail. The median age was 66 years, with patients in the present decade significantly older (68 years), on average, than patients in the three prior decades (e.g., 60 years in 1970, P = 0.02). The median tumor diameter was 3 cm; 42% of the resections had positive margins and 78% had positive lymph nodes. The perioperative morbidity was 38%. The median postoperative stay declined over time, from 16 days in the 1980s to 8 days in the 2000s (P < 0.001). The perioperative mortality declined from 30% in the 1970s to 1% in the 2000s (P < 0.001). The median survival for all patients with ductal adenocarcinoma was 18 months (1-year survival = 65 %, 2-year survival = 37%, 5-year survival = 18%). In a Cox proportional hazards model, pathological factors having a significant impact on survival included tumor diameter, resection margin status, lymph node status, and histologic grade. This is the largest single-institution experience with PD for pancreatic cancer. Patients who have cancers with favorable pathological features have a statistically significant improved long-term survival.

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A genecentric Human Protein Atlas for expression profiles based on antibodies.

Lisa Berglund, Erik Björling, Per Oksvold … (2008)

An attractive path forward in proteomics is to experimentally annotate the human protein complement of the genome in a genecentric manner. Using antibodies, it might be possible to design protein-specific probes for a representative protein from every protein-coding gene and to subsequently use the antibodies for systematical analysis of cellular distribution and subcellular localization of proteins in normal and disease tissues. A new version (4.0) of the Human Protein Atlas has been developed in a genecentric manner with the inclusion of all human genes and splice variants predicted from genome efforts together with a visualization of each protein with characteristics such as predicted membrane regions, signal peptide, and protein domains and new plots showing the uniqueness (sequence similarity) of every fraction of each protein toward all other human proteins. The new version is based on tissue profiles generated from 6120 antibodies with more than five million immunohistochemistry-based images covering 5067 human genes, corresponding to approximately 25% of the human genome. Version 4.0 includes a putative list of members in various protein classes, both functional classes, such as kinases, transcription factors, G-protein-coupled receptors, etc., and project-related classes, such as candidate genes for cancer or cardiovascular diseases. The exact antigen sequence for the internally generated antibodies has also been released together with a visualization of the application-specific validation performed for each antibody, including a protein array assay, Western blot analysis, immunohistochemistry, and, for a large fraction, immunofluorescence-based confocal microscopy. New search functionalities have been added to allow complex queries regarding protein expression profiles, protein classes, and chromosome location. The new version of the protein atlas thus is a resource for many areas of biomedical research, including protein science and biomarker discovery.

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Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB.

Jan S. Bauer, V Groh, T Spies … (1999)

Human MHC class I-related molecules, MICA and MICB, are stress-induced antigens that are recognized by a subset of gamma delta T cells expressing the variable region Vdelta1. This functional association has been found to be limited to intestinal epithelium, where these T cells are prevalent and where MICA and, presumably, MICB are mainly expressed. However, increased frequencies of Vdelta1 gamma delta T cells have been observed in various epithelial tumors; moreover, MICA/B are expressed on diverse cultured epithelial tumor cells. With freshly isolated tumor specimens, expression of MICA/B was documented in many, but not all, carcinomas of the lung, breast, kidney, ovary, prostate, and colon. In tumors that were positive for MICA/B, the frequencies of Vdelta1 gamma delta T cells were significantly higher than in those that were negative. Vdelta1 gamma delta T cell lines and clones derived from different tumors recognized MICA/B on autologous and heterologous tumor cells. In accord with previous evidence, no constraints were observed in these interactions, such as those imposed by specific peptide ligands. Thus, MICA/B are tumor-associated antigens that can be recognized, in an apparently unconditional manner, by a subset of tumor-infiltrating gamma delta T cells. These results raise the possibility that an induced expression of MICA/B, by conditions that may be related to tumor homeostasis and growth, could play a role in immune responses against tumors.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2011

Publication date (Electronic): 20 May 2011

Volume: 6

Issue: 5

Electronic Location Identifier: e20029

Affiliations

[1 ]Graduate Institute of Biomedical Sciences, Chang Gung University, Tao-Yuan, Taiwan

[2 ]Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan

[3 ]Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Tao-Yuan, Taiwan

[4 ]Divisions of General and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan

[5 ]Department of Anatomical Pathology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan

[6 ]Department of Surgery, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan

[7 ]Departments of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan

[8 ]Department of Cell and Molecular Biology, Chang Gung University, Tao-Yuan, Taiwan

The University of Kansas Medical Center, United States of America

Author notes

* E-mail: yusong@ 123456mail.cgu.edu.tw (J-SY); luckywu@ 123456mail.cgu.edu.tw (C-CW)

Conceived and designed the experiments: JSY CCW. Performed the experiments: YTC YLL MHT. Analyzed the data: YTC CCW JSY. Contributed reagents/materials/analysis tools: YMS TCC TLH TSY KPC HPL YSC. Wrote the paper: YTC CCW JSY.

Article

Publisher ID: PONE-D-11-01725

DOI: 10.1371/journal.pone.0020029

PMC ID: 3098863

PubMed ID: 21625447

SO-VID: 176c330f-a927-4107-8214-43e28bd1cfbb

Copyright © Chang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 21 January 2011

Date accepted : 10 April 2011

Page count

Pages: 10

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Secretome-Based Identification of ULBP2 as a Novel Serum Marker for Pancreatic Cancer Detection

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Abstract

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Methods

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Conclusions

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PLOS: COVID-19 pandemic

Most cited references 33

1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience.

A genecentric Human Protein Atlas for expression profiles based on antibodies.

Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB.

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Cited by 19

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