Proteomic analyses identify prognostic biomarkers for pancreatic ductal adenocarcinoma
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Dingyuan Hu1,2, Daniel Ansari3, Krzysztof Pawłowski4,5, Qimin Zhou1, Agata Sasor6, Charlotte Welinder7, Theresa Kristl7, Monika Bauden1, Melinda Rezeli8, Yi Jiang2, György Marko-Varga8 and Roland Andersson3
1Lund University, Faculty of Medicine, Department of Clinical Sciences Lund (Surgery), Lund, Sweden
2Department of Gastroenterology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
3Lund University, Skane University Hospital, Department of Clinical Sciences Lund (Surgery), Lund, Sweden
4Department of Experimental Design and Bioinformatics, Warsaw University of Life Sciences, Warsaw, Poland
5Department of Translational Medicine, Lund University, Malmö, Sweden
6Department of Pathology, Skåne University Hospital, Lund, Sweden
7Lund University, Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund, Sweden
8Department of Biomedical Engineering, Clinical Protein Science and Imaging, Lund University, Lund, Sweden
Roland Andersson, email: [email protected]
Keywords: pancreatic ductal adenocarcinoma; survival; biomarker; proteome; tumor microenvironment
Received: September 19, 2017 Accepted: October 27, 2017 Published: January 03, 2018
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Here we show that shotgun and targeted protein sequencing can be used to identify potential prognostic biomarkers in formalin-fixed paraffin-embedded specimens from 9 patients with PDAC with “short” survival (<12 months) and 10 patients with “long” survival (>45 months) undergoing surgical resection. A total of 24 and 147 proteins were significantly upregulated [fold change ≥2 or ≤0.5 and P<0.05; or different detection frequencies (≥5 samples)] in patients with “short” survival (including GLUT1) and “long” survival (including C9orf64, FAM96A, CDH1 and CDH17), respectively. STRING analysis of these proteins indicated a tight protein-protein interaction network centered on TP53. Ingenuity pathway analysis linked proteins representing “activated stroma factors” and “basal tumor factors” to poor prognosis of PDAC. It also highlighted TCF1 and CTNNB1 as possible upstream regulators. Further parallel reaction monitoring verified that seven proteins were upregulated in patients with “short” survival (MMP9, CLIC3, MMP8, PRTN3, P4HA2, THBS1 and FN1), while 18 proteins were upregulated in patients with “long” survival, including EPCAM, LGALS4, VIL1, CLCA1 and TPPP3. Thus, we verified 25 protein biomarker candidates for PDAC prognosis at the tissue level. Furthermore, an activated stroma status and protein-protein interactions with TP53 might be linked to poor prognosis of PDAC.
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