Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada.
Inflamm Bowel Dis. 2022 Oct 3;28(10):1485-1496. doi: 10.1093/ibd/izac098.
Ulcerative colitis (UC) is a progressive disorder that elevates the risk of colon cancer development through a colitis-dysplasia-carcinoma sequence. Gene expression profiling of colitis-associated lesions obtained from patients with varied extents of UC can be mined to define molecular panels associated with colon cancer development.
Differential gene expression profiles of 3 UC clinical subtypes and healthy controls were developed for the GSE47908 microarray data set of healthy controls, left-sided colitis, pancolitis, and colitis-associated dysplasia (CAD) using limma R.
A gene ontology enrichment analysis of differentially expressed genes (DEGs) revealed a shift in the transcriptome landscape as UC progressed from left-sided colitis to pancolitis to CAD, from being immune-centric to being cytoskeleton-dependent. Hippo signaling (via Yes-associated protein [YAP]) and Ephrin receptor signaling were the top canonical pathways progressively altered in concert with the pathogenic progression of UC. A molecular interaction network analysis of DEGs in left-sided colitis, pancolitis, and CAD revealed 1 pairwise line, or edge, that was topologically important to the network structure. This edge was found to be highly enriched in actin-based processes, and death-associated protein kinase 3 (DAPK3) was a critical member and sole protein kinase member of this network. Death-associated protein kinase 3 is a regulator of actin-cytoskeleton reorganization that controls proliferation and apoptosis. Differential correlation analyses revealed a negative correlation for DAPK3-YAP in healthy controls that flipped to positive in left-sided colitis. With UC progression to CAD, the DAPK3-YAP correlation grew progressively more positive.
In summary, DAPK3 was identified as a candidate gene involved in UC progression to dysplasia.
溃疡性结肠炎（UC）是一种进行性疾病，通过结肠炎-异型增生-癌序列增加结肠癌发展的风险。对来自 UC 程度不同的患者的结肠炎相关病变进行基因表达谱分析，可以确定与结肠癌发展相关的分子谱。
使用 limma R 对健康对照、左侧结肠炎、全结肠炎和结肠炎相关异型增生（CAD）的 GSE47908 微阵列数据集进行 3 种 UC 临床亚型和健康对照的差异基因表达谱开发。
差异表达基因（DEGs）的基因本体富集分析显示，随着 UC 从左侧结肠炎发展到全结肠炎再到 CAD，转录组图谱发生了变化，从以免疫为中心转变为依赖细胞骨架。Hippo 信号（通过 Yes 相关蛋白[YAP]）和 Ephrin 受体信号是与 UC 发病进展协同逐渐改变的顶级经典途径。左侧结肠炎、全结肠炎和 CAD 中 DEGs 的分子相互作用网络分析显示，拓扑结构上对网络结构很重要的有 1 条平行线或边。该边在基于肌动蛋白的过程中高度富集，死亡相关蛋白激酶 3（DAPK3）是该网络的关键成员和唯一蛋白激酶成员。死亡相关蛋白激酶 3是控制增殖和凋亡的肌动蛋白-细胞骨架重排的调节剂。差异相关分析显示，在健康对照组中，DAPK3-YAP 呈负相关，在左侧结肠炎中呈正相关。随着 UC 向 CAD 的进展，DAPK3-YAP 的相关性变得越来越正。
总之，DAPK3 被确定为参与 UC 向异型增生进展的候选基因。
