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

Yin Zhang; Chun-Yuan Li; Meng Pan; Jing-Ying Li; Wei Ge; Lai Xu; Yi Xiao

doi:10.1155/2021/5538756

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

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

Authors

Yin Zhang¹, Chun-Yuan Li², Meng Pan², Jing-Ying Li¹, Wei Ge^{2

3}, Lai Xu¹, Yi Xiao¹

Affiliations

¹ Division of Colorectal Surgery, Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² State Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
³ Hebei Key Laboratory of Chronic Kidney Diseases and Bone Metabolism, Affiliated Hospital of Hebei University, Baoding, China.

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.