Abstract
The global change in protein abundance in colorectal cancer (CRC) and its contribution to tumorigenesis have not been comprehensively analyzed. In this study, we conducted a comprehensive proteomic analysis of paired tumors and adjacent tissues (AT) using high-resolution Fourier-transform mass spectrometry and a novel algorithm of quantitative pathway analysis. 12380 proteins were identified and 740 proteins that presented a 4-fold change were considered a CRC proteomic signature. A significant pattern of changes in protein abundance was uncovered which consisted of an imbalance in protein abundance of inhibitory and activating regulators in key signal pathways, a significant elevation of proteins in chromatin modification, gene expression and DNA replication and damage repair, and a decreased expression of proteins responsible for core extracellular matrix architectures. Specifically, based on the relative abundance, we identified a panel of 11 proteins to distinguish CRC from AT. The protein that showed the greatest degree of overexpression in CRC compared to AT was Dipeptidase 1 (DPEP1). Knockdown of DPEP1 in SW480 and HCT116 cells significantly increased cell apoptosis and attenuated cell proliferation and invasion. Together, our results show one of largest dataset in CRC proteomic research and provide a molecular link from genomic abnormalities to the tumor phenotype.
Highlights
Membrane-bound Dipeptidase 1 (DPEP1, known as microsomal dipeptidase or renal dipeptidase) is a zinc-dependent metalloproteinase that has been shown to process a plethora of peptides and antibiotics, as well as to be involved in the glutathione and leukotriene metabolism
Quantitative proteomic analysis reveals a significant pattern of changes in protein abundance in the colorectal cancer (CRC) proteome
8,832 proteins were detected in both CRCs and adjacent tissues (AT), 10,030 proteins were detected in ATs, and 11,183 proteins were detected in CRCs (Fig. 1A and Supplementary Dataset 1 and 2)
Summary
Membrane-bound Dipeptidase 1 (DPEP1, known as microsomal dipeptidase or renal dipeptidase) is a zinc-dependent metalloproteinase that has been shown to process a plethora of peptides and antibiotics, as well as to be involved in the glutathione and leukotriene metabolism. The encoded protein is anchored to the membrane by a covalently attached glycosyl-phosphatidylinositol moiety and has a highly hydrophobic sequence located at its carboxyl terminus. We investigated DPEP1 as a candidate marker in CRC. Our study provides a useful database for CRC biomarker discovery and provides new insights into DPEP1-mediated cancer progression
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