Table_2_Upregulation of ADAM12 Is Associated With a Poor Survival and Immune Cell Infiltration in Colon Adenocarcinoma.docx

BackgroundA disintegrin and metalloprotease 12 (ADAM12) is a member of the multidomain protein family, but the mechanisms by which it affects prognosis and immune cell infiltration in patients with colon adenocarcinoma (COAD) remain unclear. Here, our study aimed to analyze the prognostic value of ADAM12 and investigate the correlation between ADAM12 expression and immune cell infiltration in patients with COAD.
MethodsDifferential expression analyses were performed using the Oncomine and UALCAN databases, and prognostic analyses were conducted using PrognoScan, Gene Expression Profiling Interactive Analysis (GEPIA), and Kaplan–Meier Plotter. Then, the cBioPortal database was used to analyze alterations in the ADAM12 gene, and the STRING and Metascape websites were used to conduct Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Additionally, relationships between ADAM12 and the immune microenvironment were evaluated based on the TIMER, GEPIA, and TISIDB databases.
ResultsADAM12 was overexpressed in COAD tissues, and higher ADAM12 expression correlated with a worse prognosis for patients with COAD. The gene regulatory network suggested that ADAM12 was mainly enriched in extracellular matrix (ECM) organization, ECM proteoglycans, skeletal system development, and ossification, among other pathways. Moreover, ADAM12 expression significantly correlated with the abundance of CD4+ T cells, B cells, CD8+ T cells, neutrophils, macrophages, dendritic cells, and their markers, as well as lymphocytes, immunomodulators, and chemokines.
ConclusionsIn colorectal tumors, ADAM12 may play vital roles in regulating the ECM and the recruitment of immune cells, and we suggest that ADAM12 will become a reliable biomarker for determining response to immunotherapy and the prognosis of patients with COAD.

背景：解整合素-金属蛋白酶12（ADAM12）属于多结构域蛋白家族，但其调控结肠腺癌（colon adenocarcinoma，COAD）患者预后及影响免疫细胞浸润的分子机制尚未明确。本研究旨在分析ADAM12的预后价值，并探讨ADAM12表达与结肠腺癌患者免疫细胞浸润的相关性。
方法：采用Oncomine及UALCAN数据库开展差异表达分析，借助PrognoScan、基因表达谱交互分析（Gene Expression Profiling Interactive Analysis，GEPIA）及Kaplan–Meier Plotter工具进行预后分析；随后通过cBioPortal数据库分析ADAM12基因的变异情况，并利用STRING及Metascape平台开展基因本体（Gene Ontology，GO）与京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）富集分析；此外，基于TIMER、GEPIA及TISIDB数据库评估ADAM12与肿瘤免疫微环境的关联。
结果：ADAM12在结肠腺癌组织中呈高表达，且ADAM12高表达与结肠腺癌患者不良预后显著相关。基因调控网络分析显示，ADAM12主要富集于细胞外基质（extracellular matrix，ECM）组织、ECM蛋白聚糖、骨骼系统发育及骨化等通路。此外，ADAM12表达与CD4+ T细胞、B细胞、CD8+ T细胞、中性粒细胞、巨噬细胞、树突状细胞及其标志物的浸润丰度，以及淋巴细胞、免疫调节因子及趋化因子的表达水平均存在显著相关性。
结论：在结直肠肿瘤中，ADAM12可能在调控细胞外基质（ECM）及免疫细胞招募过程中发挥关键作用，本研究提示ADAM12可作为预测结肠腺癌患者免疫治疗应答及预后的可靠生物标志物。