Quantitative proteomics investigation of pancreatic intraepithelial neoplasia

Abstract

Patients with pancreatic cancer are usually diagnosed at late stages, when the disease is incurable. Pancreatic intraepithelial neoplasia (PanIN) 3, is believed to be the immediate precursor lesion of pancreatic adenocarcinoma, and would be an ideal stage to diagnose patients, when intervention and cure are possible and patients are curable. In this study, we used quantitative proteomics to identify dysregulated proteins in PanIN 3 lesions. Altogether, over 200 dysregulated proteins were identified in the PanIN 3 tissues, with a minimum of a 1.75 fold change compared to the proteins in normal pancreas. These dysregulated PanIN 3 proteins play roles in cell motility, the inflammatory response, the blood clotting cascade, the cell cycle and its regulation, and protein degradation. Further network analysis of the proteins identified c-MYC as an important regulatory protein in PanIN 3 lesions. Finally, three of the overexpressed proteins, laminin beta-1, galectin-1, and actinin-4 were validated by IHC analysis. All three of these proteins were overexpressed in the stroma or ductal epithelial cells of advanced PanIN lesions, as well as in pancreatic cancer tissue. Our findings suggest that these three proteins may be useful as biomarkers for advanced PanIN and pancreatic cancer if further validated. The dysregulated proteins identified in this study may assist in the selection of candidates for future development of biomarkers for detecting early and curable pancreatic neoplasia.

Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma

“…Although these studies demonstrate the importance of deregulated Myc signaling in PDAC, our results suggest an early role during PanIN progression supported by early Myc amplification in precursor lesions (38). In a recent quantitative proteomic screen of preneoplastic PanIN lesions, Myc expression was identified in PanIN3 lesions (43).…”

Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma

“…The two pooled samples were labeled with iTRAQ stable isotope tags individually, then combined, subjected to subsequent fractionation and purification, followed by mass spectrometry analysis as described previously. 24 Quantitative proteomics based on a LC MALDI TOF/ TOF analysis revealed 26 differentially expressed proteins at ≥ 1.5-fold: 11 were overexpressed and 15 were under-expressed in VLTS ( Table 1).…”

“…Some of these differentially expressed proteins, namely galectin 1 (LGALS1), thrombospondin 1 (THBS1) and S100A4 have previously been reported to be overexpressed in PDAC tissues. 24,27,28 Among these differentially expressed proteins, the expression of galectin-1 (LGALS1) was almost 2-fold higher in the STS pool compared with matched VLTS pool (Fig. 1).…”

“…Related to this observation, we have previously identified increased galectin-1 expression in the stroma of PanIN lesions and stroma of PDAC. 24 Previous studies have reported the association between galectin-1 upregulation and advanced histological grade, systemic metastases, and immune evasion in the tumor microenvironment. [29][30][31] Base on these observations, we chose to further investigate galectin-1 in the context of PDAC patient survival.…”

Targeted diagnostic magnetic nanoparticles for medical imaging of pancreatic cancer

“…The expression of Gal-1 was reported to be upregulated in pancreatic cancer cells but is not expressed in adjacent normal tissues or adjacent inflammatory pancreas [18,19].…”