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. 2021 Nov 29:2021:5538756.
doi: 10.1155/2021/5538756. eCollection 2021.

Exploration of the Key Proteins of High-Grade Intraepithelial Neoplasia to Adenocarcinoma Sequence Using In-Depth Quantitative Proteomics Analysis

Yin Zhang  1 , Chun-Yuan Li  2 , Meng Pan  2 , Jing-Ying Li  1 , Wei Ge  2   3 , Lai Xu  1 , Yi Xiao  1
Affiliations

Exploration of the Key Proteins of High-Grade Intraepithelial Neoplasia to Adenocarcinoma Sequence Using In-Depth Quantitative Proteomics Analysis

Yin Zhang et al. J Oncol. .

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.

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Conflict of interest statement

The authors declare no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Heatmap of the highly expressed proteins in HIN-AC sequence. Heatmap showing the relative abundance of 536 proteins in the normal mucosa (NM), high-grade intraepithelial neoplasia (HIN), and adenocarcinoma (AC) group. The proteins were clustered hierarchically by Pearson correlation analysis. Green indicates downregulated proteins, whereas red indicates upregulated proteins. C: cluster.
Figure 2
Figure 2
Pathway enrichment analysis of the proteins increasingly expressed in NM-HIN-AC sequence. Kyoto encyclopedia of gene (KEGG) and Reactome pathway analyses of cluster 2 were performed using the ClueGO and CluePedia plugins in Cytoscape. Circles shown in the same color represent similar enrichment results.
Figure 3
Figure 3
Identification of the core clusters of the proteins upregulated in the NM-HIN-AC sequence. (a) Protein-protein interaction (PPI) network of the proteins upregulated in the NM-HIN-AC sequence was constructed using STRING. The top 3 clusters were identified using the MCODE plugin in Cytoscape. (b–d) Enrichment analysis of MCODE1-MCODE3 using Metascape.
Figure 4
Figure 4
Validation of the expression of SERPINH1 and P3H1 in the GEO database. (a) The expression of SERPINH1 and P3H1 was significantly upregulated in the HIN-AC sequence in the GSE 41657 dataset. (b) The expression of SERPINH1 and P3H1 was significantly upregulated in the HIN-AC sequence in the GSE 37364 dataset.
Figure 5
Figure 5
Correlation analysis of the expression of SERPINH1 and P3H1 and the abundance of immune infiltrating cells. (a) Spearman's correlation analysis of SERPINH1 expression and the abundance of immune infiltrating cells using the MCP-counter algorithm. (b) Spearman's correlation analysis of P3H1 expression and the abundance of immune infiltrating cells using the MCP-counter algorithm. NK cell, natural killer cell; CAF, cancer associated fibroblasts.
Figure 6
Figure 6
Correlation analysis of the expression of SERPINH1 and P3H1 and the expression of common CRC immune checkpoints. (a) Pearson correlation analysis of the expression of SERPINH1 and PDCD1, CD274, CTLA4, HAVCR2, LAG3, and TIGIT in the GEPIA database. (b) Pearson correlation analysis of the expression of P3H1 and PDCD1, CD274, CTLA4, HAVCR2, LAG3, and TIGIT in the GEPIA database.
Figure 7
Figure 7
Expression of SERPINH1 and P3H1 in different consensus molecular subtypes (CMS) of CRC. The expression of SERPINH1 (a) and P3H1 (b) was significantly upregulated in CMS4 of CRC in TCGA cohort.
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