Background: Cholangiocarcinoma (CCA) are aggressive bile duct cancers with a poor prognosis for which there are only few established prognostic biomarkers and molecular targets available. The geneITIH5, a known class II tumor suppressor gene (C2TSG), encodes a secreted protein of the extracellular matrix mediating tumor suppressive properties. Recently, it was surprisingly found that the ITIH5 protein is specifically upregulated in CCAs and that ITIH5 detection in blood could be an excellent liquid biopsy marker for indicating the presence of a CCA tumor in a patient. We therefore investigated whether patients with CCAs with abundant versus low ITIH5 protein expression also differ in their prognosis.Methods: To clarify this question, a large CCA cohort (n = 175) was examined using immunohistochemistry on a tissue microarray (TMA).Results: Abundant ITIH5 expression in CCA was associated with favorable survival, a low UICC stage and the absence of perineural invasion (PNI).Conclusions: ITIH5 has biomarker potential not only for the early detection of CCA from blood-based liquid biopsies but also as a prognostic tissue biomarker for risk stratification. Our results suggest that the upregulation of ITIH5 is particularly abundant in intrahepatic CCAs (iCCA). The mechanisms mediating the strong initial upregulation of ITIH5 during the oncogenic transformation of bile duct cells are still unclear.
背景：胆管癌（CCA）是一种侵袭性胆管癌，预后较差，目前仅有少数已确立的预后生物标志物和分子靶点可供使用。基因ITIH5作为一种已知的II类肿瘤抑制基因（C2TSG），编码一种细胞外基质分泌蛋白，介导肿瘤抑制特性。近期研究发现，ITIH5蛋白在CCA中特异性上调，且血液中ITIH5的检测可能成为指示患者存在CCA肿瘤的优异液体活检标志物。因此，我们研究了ITIH5蛋白高表达与低表达的CCA患者是否在预后方面存在差异。 方法：为阐明这一问题，我们采用组织芯片（TMA）免疫组化技术对大型CCA队列（n=175）进行了检测。 结果：CCA中ITIH5的高表达与良好生存率、低UICC分期以及无神经周围浸润（PNI）相关。 结论：ITIH5不仅具有通过血液液体活检早期检测CCA的生物标志物潜力，还可作为风险分层的预后组织生物标志物。我们的研究结果表明，ITIH5的上调在肝内胆管癌（iCCA）中尤为显著。胆管细胞癌变过程中介导ITIH5强烈初始上调的机制尚不清楚。
肿瘤(癌症)患者之家