Cholangiocarcinoma often remains undetected until advanced stages due to the lack of reliable diagnostic markers. Our goal was to identify a unique secretory protein for cholangiocarcinoma diagnosis and differentiation from other malignancies, benign hepatobiliary diseases, and chronic liver conditions. We conducted bulk RNA‐seq analysis to identify genes specifically upregulated in cholangiocarcinoma but not in most other cancers, benign hepatobiliary diseases, and chronic liver diseases focusing on exocrine protein‐encoding genes. Single‐cell RNA sequencing examined subcellular distribution. Immunohistochemistry and enzyme‐linked immunosorbent assays assessed tissue and serum expression. Diagnostic performance was evaluated via receiver‐operating characteristic (ROC) analysis. Inter‐alpha‐trypsin inhibitor heavy chain family member five (ITIH5), a gene encoding an extracellular protein, is notably upregulated in cholangiocarcinoma. This elevation is not observed in most other cancer types, benign hepatobiliary diseases, or chronic liver disorders. It is specifically expressed by malignant cholangiocytes. ITIH5 expression in cholangiocarcinoma tissues exceeded that in nontumorous bile duct, hepatocellular carcinoma, and nontumorous hepatic tissues. Serum ITIH5 levels were elevated in cholangiocarcinoma compared with controls (hepatocellular carcinoma, benign diseases, chronic hepatitis B, and healthy individuals). ITIH5 yielded areas under the ROC curve (AUCs) from 0.839 to 0.851 distinguishing cholangiocarcinoma from controls. Combining ITIH5 with carbohydrate antigen 19‐9 (CA19‐9) enhanced CA19‐9's diagnostic effectiveness. In conclusion, serum ITIH5 may serve as a novel noninvasive cholangiocarcinoma diagnostic marker.

中文翻译：

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血清 ITIH5 作为胆管癌的新型诊断生物标志物

由于缺乏可靠的诊断标志物，胆管癌通常直到晚期才被发现。我们的目标是确定一种独特的分泌蛋白，用于胆管癌的诊断以及与其他恶性肿瘤、良性肝胆疾病和慢性肝脏疾病的鉴别。我们进行了大量 RNA 测序分析，以确定在胆管癌中特异性上调的基因，但在大多数其他癌症、良性肝胆疾病和慢性肝病中不上调，重点关注外分泌蛋白编码基因。单细胞 RNA 测序检查了亚细胞分布。免疫组织化学和酶联免疫吸附测定评估组织和血清表达。通过接受者操作特征（ROC）分析评估诊断性能。间α胰蛋白酶抑制剂重链家族成员五（ITIH5）是一种编码细胞外蛋白的基因，在胆管癌中显着上调。在大多数其他癌症类型、良性肝胆疾病或慢性肝脏疾病中未观察到这种升高。它由恶性胆管细胞特异性表达。ITIH5在胆管癌组织中的表达高于非肿瘤胆管、肝细胞癌和非肿瘤肝组织。与对照（肝细胞癌、良性疾病、慢性乙型肝炎和健康个体）相比，胆管癌中的血清 ITIH5 水平升高。ITIH5 产生的 ROC 曲线下面积 (AUC) 为 0.839 至 0.851，可区分胆管癌和对照。将 ITIH5 与碳水化合物抗原 19-9 (CA19-9) 结合增强了 CA19-9 的诊断有效性。总之，血清ITIH5可能作为一种新型的非侵袭性胆管癌诊断标志物。