Abstract
Proteolytic cascades are deeply involved in critical stages of cancer progression. During the course of peptide-wise analysis of shotgun proteomic data sets representative of colon adenocarcinoma (AC) and ulcerative colitis (UC), we detected a cancer-specific proteolytic fingerprint composed of a set of numerous protein fragments cleaved C-terminally to V, I, A, T, or C residues, significantly overrepresented in AC. A peptide set linked by a common VIATC cleavage consensus was the only prominent cancer-specific proteolytic fingerprint detected. This sequence consensus indicated neutrophil elastase as a source of the fingerprint. We also found that a large fraction of affected proteins are RNA processing proteins associated with the nuclear fraction and mostly cleaved within their functionally important RNA-binding domains. Thus, we detected a new class of cancer-specific peptides that are possible markers of tumor-infiltrating neutrophil activity, which often correlates with the clinical outcome. Data are available via ProteomeXchange with identifiers: PXD005274 (Data set 1) and PXD004249 (Data set 2). Our results indicate the value of peptide-wise analysis of large global proteomic analysis data sets as opposed to protein-wise analysis, in which outlier differential peptides are usually neglected.
Highlights
Cancer-specific proteolytic activity is one of the highlights of cancer progression, and specific changes in the tumor degradosome may serve as a reservoir for potential diagnostic molecular features (1)
In the course of peptide-wise proteomic analyses of AC samples, we detected abundant cancer-specific proteolytic events that strictly fulfill the cleavage consensus VIATC characteristic for neutrophil elastase
We have shown that cancer-specific elastase cleavage mostly affects the nuclear fraction of AC tumor tissue, with multiple RNPs affected and many cleavage sites localized within functionally important RRM RNA-binding domains
Summary
Cancer-specific proteolytic activity is one of the highlights of cancer progression, and specific changes in the tumor degradosome may serve as a reservoir for potential diagnostic molecular features (1). Search parameters were: mass tolerances calculated individually for each sample; enabled decoy search; no enzyme specificity; fixed modification - cysteine carbamidomethylation; variable modifications defined as methionine oxidation, N-terminal acetylation, and glutamine substitution by pyroGlu. Following the extraction of peptides fulfilling the criterion of FDR< 1%, (peptides and proteins identified are listed in Supporting Material Table S4) the quantitative analysis was carried out using a “spectral count” approach (25).
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