Abstract
Purpose In this study, we aimed to provide a comprehensive description of typical features and identify key proteins associated with the high-grade intraepithelial neoplasia- (HIN-) adenocarcinoma (AC) sequence. Methods We conducted tandem mass tag-based quantitative proteomic profiling of normal mucosa, HIN, and AC tissues. Protein clusters representative of the HIN-AC sequence were identified using heatmaps based on Pearson's correlation analysis. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database, ClueGO plugin in Cytoscape, and the Metascape database. The prognostic value of the key proteins and their effects on the tumor microenvironment and consensus molecular subtype were explored based on The Cancer Genome Atlas. Results We identified 536 proteins categorized into three clusters. Among the biological processes and pathways of the highly expressed proteins in the HIN-AC sequence, proteins were predominantly enriched in response to gut microbiota, cell proliferation, leukocyte migration, and extracellular matrix (ECM) organization events. SERPINH1 and P3H1 were identified as the key proteins that promote the HIN-AC sequence. In the correlation analysis of infiltrating immune cells, both SERPINH1 and P3H1 expression correlated negatively with tumor purity, while correlating positively with abundance of CD8+ T cells, B cells, macrophage/monocytes, dendritic cells, cancer-associated fibroblasts, endothelial cells, neutrophils, and natural killer cells. Furthermore, both SERPINH1 and P3H1 expression positively correlated with common immune checkpoints and mesenchymal molecular subtype. High P3H1 expression was associated with poor disease-free survival and overall survival. Conclusions ECM-related biological processes and pathways are typical features of the HIN-AC sequence. SERPINH1 and P3H1 might be the key proteins in this sequence and be related to ECM remodeling and immune suppression status in CRC.
Highlights
Colorectal cancer (CRC) is the second leading cause of all cancer deaths, accounting for 9.2% worldwide [1]
Zhang et al found that mTOR, p70s6 K, and 4EBP1 were highly expressed in High-grade intraepithelial neoplasia (HIN) and CRC compared with normal mucosa (NM), and mTOR gene silencing was implicated as a novel therapeutic strategy for CRC [6]
SERPINH1 and P3H1 were identified as the intersection proteins using the maximal clique centrality (MCC), density of maximum neighborhood component (DMNC), maximum neighborhood component (MNC), and clustering coefficient methods in CytoHubba (Table S2). us, we regarded SERPINH1 and P3H1 as key proteins in the HIN to AC process
Summary
Colorectal cancer (CRC) is the second leading cause of all cancer deaths, accounting for 9.2% worldwide [1]. Many studies have focused on the markers that show diagnostic value or have been identified as therapeutic targets in the normal adenoma-carcinoma sequence. Dipeptidase 1 (DPEP1) was upregulated in HIN and CRC compared with low-grade intraepithelial neoplasia and NM [7]. Other studies have investigated proteins that could be both early diagnostic markers in adenoma carcinogenesis and prognostic markers in CRC [8,9,10]. These studies did not focus on the HIN-AC sequence in carcinogenesis. E HIN-AC sequence is the advanced phase of carcinogenesis and the proteins or/ and pathways involved might be both preventive and therapeutic target. We aimed to provide a comprehensive description of the key proteins involved in the HIN-AC sequence
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