Objectives: Forkhead transcription factor, O subgroup, member 1 (FOXO1) is a regulatory protein that plays an essential role in cellular homeostasis. A biological function as a tumor suppressor has been proposed. Here, we examined FOXO1 expression in human pancreatic ductal adenocarcinoma (PDAC) and its precursor lesions. Methods: We immunohistochemically labeled tissue samples from 47 patients with PDAC for FOXO1 protein. In addition, we extracted data from the Cancer Genome Atlas and the Cancer Cell Line Encyclopedia and studied a potential association with well-established genetic variants. A publicly available microarray dataset of 102 PDAC samples was used to explore the influence of FOXO1 expression on patients’ clinical outcome. Results: Normal ductal epithelium universally expressed nuclear and cytoplasmic FOXO1. Reduced expression was observed in PanIN lesions and PDAC of all cases. Analysis of several datasets showed that the FOXO1 gene transcript levels do not correlate with KRAS, TP53, SMAD4, or CDKN2A mutation status, but positively correlate with patients’ outcomes. Conclusions: Loss of FOXO1 protein is identified as an early event during PDAC development and may be independent of the top 4 mutated cancer genes. Because of its strong expression in normal ductal cells, immunohistochemical detection of FOXO1 can function as a valuable test to establish the diagnosis of transformation and malignancy in pancreatic tissues.

中文翻译：

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叉头转录因子、O 亚组、成员 1 蛋白在胰管腺癌发展过程中的早期丢失


目的：叉头转录因子，O 亚组，成员 1 (FOXO1) 是一种调节蛋白，在细胞稳态中发挥重要作用。已提出作为肿瘤抑制因子的生物学功能。在这里，我们检测了 FOXO1 在人胰腺导管腺癌 (PDAC) 及其癌前病变中的表达。方法：我们对 47 名 PDAC 患者的组织样本进行 FOXO1 蛋白免疫组织化学标记。此外，我们还从癌症基因组图谱和癌细胞系百科全书中提取数据，并研究了与已确定的遗传变异的潜在关联。使用包含 102 个 PDAC 样本的公开微阵列数据集来探讨 FOXO1 表达对患者临床结果的影响。结果：正常导管上皮细胞核和细胞质普遍表达 FOXO1。所有病例的 PanIN 病灶和 PDAC 中均观察到表达减少。对多个数据集的分析表明，FOXO1 基因转录水平与 KRAS、TP53、SMAD4 或 CDKN2A 突变状态不相关，但与患者的预后呈正相关。结论：FOXO1 蛋白的缺失被确定为 PDAC 发育过程中的早期事件，并且可能与前 4 个突变的癌症基因无关。由于 FOXO1 在正常导管细胞中强表达，因此 FOXO1 的免疫组织化学检测可以作为诊断胰腺组织转化和恶性肿瘤的有价值的测试。