Inter‐alpha‐trypsin inhibitor heavy chain 5 (ITIH5) has been identified as a metastasis suppressor gene in pancreatic cancer. Here, we analyzed ITIH5 promoter methylation and protein expression in The Cancer Genome Atlas (TCGA) dataset and three tissue microarray cohorts (n = 618), respectively. Cellular effects, including cell migration, focal adhesion formation and protein tyrosine kinase activity, induced by forced ITIH5 expression in pancreatic cancer cell lines were studied in stable transfectants. ITIH5 promoter hypermethylation was associated with unfavorable prognosis, while immunohistochemistry demonstrated loss of ITIH5 in the metastatic setting and worsened overall survival. Gain‐of‐function models showed a significant reduction in migration capacity, but no alteration in proliferation. Focal adhesions in cells re‐expressing ITIH5 exhibited a smaller and more rounded phenotype, typical for slow‐moving cells. An impressive increase of acetylated alpha‐tubulin was observed in ITIH5‐positive cells, indicating more stable microtubules. In addition, we found significantly decreased activities of kinases related to focal adhesion. Our results indicate that loss of ITIH5 in pancreatic cancer profoundly affects its molecular profile: ITIH5 potentially interferes with a variety of oncogenic signaling pathways, including the PI3K/AKT pathway. This may lead to altered cell migration and focal adhesion formation. These cellular alterations may contribute to the metastasis‐inhibiting properties of ITIH5 in pancreatic cancer.

中文翻译：

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ITIH5 在抑制胰腺癌、损害酪氨酸激酶信号传导、细胞粘附和迁移方面发挥多方面作用

间α-胰蛋白酶抑制剂重链5（ITIH5）已被鉴定为胰腺癌的转移抑制基因。在这里，我们分析了ITIH5癌症基因组图谱 (TCGA) 数据集和三个组织微阵列队列中的启动子甲基化和蛋白质表达（n= 618），分别。强制诱导的细胞效应，包括细胞迁移、粘着斑形成和蛋白酪氨酸激酶活性ITIH5在稳定转染子中研究了胰腺癌细胞系中的表达。ITIH5启动子高甲基化与不良预后相关，而免疫组织化学显示转移环境中 ITIH5 丢失并恶化总体生存率。功能获得模型显示迁移能力显着降低，但增殖能力没有改变。细胞重新表达的粘着斑ITIH5表现出更小、更圆的表型，这是缓慢移动细胞的典型特征。在 ITIH5 阳性细胞中观察到乙酰化 α 微管蛋白显着增加，表明微管更加稳定。此外，我们发现与粘着斑相关的激酶活性显着降低。我们的结果表明，胰腺癌中 ITIH5 的缺失深刻影响其分子特征：ITIH5 可能干扰多种致癌信号通路，包括 PI3K/AKT 通路。这可能导致细胞迁移和粘着斑形成的改变。这些细胞改变可能有助于 ITIH5 在胰腺癌中的转移抑制特性。