Zhang Yin, Li Chun-Yuan, Pan Meng, Li Jing-Ying, Ge Wei, Xu Lai, Xiao Yi
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.
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.
J Oncol. 2021 Nov 29;2021:5538756. doi: 10.1155/2021/5538756. eCollection 2021.
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.
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.
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.
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.
在本研究中，我们旨在全面描述典型特征，并识别与高级别上皮内瘤变-腺癌（HIN-AC）序列相关的关键蛋白。
我们对正常黏膜、HIN和AC组织进行了基于串联质谱标签的定量蛋白质组分析。基于Pearson相关分析，使用热图识别代表HIN-AC序列的蛋白质簇。使用注释、可视化和综合发现数据库（DAVID）、Cytoscape中的ClueGO插件以及Metascape数据库进行基因本体（GO）、京都基因与基因组百科全书（KEGG）和Reactome分析。基于癌症基因组图谱探讨关键蛋白的预后价值及其对肿瘤微环境和共识分子亚型的影响。
我们鉴定出536种蛋白质，分为三个簇。在HIN-AC序列中高表达蛋白质的生物学过程和通路中，蛋白质主要富集于对肠道微生物群的反应、细胞增殖、白细胞迁移和细胞外基质（ECM）组织事件。SERPINH1和P3H1被鉴定为促进HIN-AC序列的关键蛋白。在浸润性免疫细胞的相关性分析中，SERPINH1和P3H1的表达均与肿瘤纯度呈负相关，而与CD8 T细胞、B细胞、巨噬细胞/单核细胞、树突状细胞、癌症相关成纤维细胞、内皮细胞、中性粒细胞和自然杀伤细胞的丰度呈正相关。此外，SERPINH1和P3H1的表达均与常见免疫检查点和间充质分子亚型呈正相关。高P3H1表达与无病生存期和总生存期较差相关。
ECM相关的生物学过程和通路是HIN-AC序列的典型特征。SERPINH1和P3H1可能是该序列中的关键蛋白，与结直肠癌中的ECM重塑和免疫抑制状态相关。
