Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Hepatology. 2024 Feb 1;79(2):307-322. doi: 10.1097/HEP.0000000000000437. Epub 2023 May 5.
Cholangiocarcinoma (CCA) is a highly lethal malignancy originating from the biliary ducts. Current CCA diagnostic and prognostic assessments cannot satisfy the clinical requirement. Bile detection is rarely performed, and herein, we aim to estimate the clinical significance of bile liquid biopsy by assessing bile exosomal concentrations and components.
Exosomes in bile and sera from CCA, pancreatic cancer, and common bile duct stone were identified and quantified by transmission electronmicroscopy, nanoparticle tracking analysis, and nanoFCM. Exosomal components were assessed by liquid chromatography with tandem mass spectrometry and microRNA sequencing (miRNA-seq). Bile exosomal concentration in different diseases had no significant difference, but miR-182-5p and miR-183-5p were ectopically upregulated in CCA bile exosomes. High miR-182/183-5p in both CCA tissues and bile indicates a poor prognosis. Bile exosomal miR-182/183-5p is secreted by CCA cells and can be absorbed by biliary epithelium or CCA cells. With xenografts in humanized mice, we showed that bile exosomal miR-182/183-5p promotes CCA proliferation, invasion, and epithelial-mesenchymal transition (EMT) by targeting hydroxyprostaglandin dehydrogenase in CCA cells and mast cells (MCs), and increasing prostaglandin E2 generation, which stimulates PTGER1 and increases CCA stemness. In single-cell mRNA-seq, hydroxyprostaglandin dehydrogenase is predominantly expressed in MCs. miR-182/183-5p prompts MC to release VEGF-A release from MC by increasing VEGF-A expression, which facilitates angiogenesis.
CCA cells secret exosomal miR-182/183-5p into bile, which targets hydroxyprostaglandin dehydrogenase in CCA cells and MCs and increases prostaglandin E2 and VEGF-A release. Prostaglandin E2 promotes stemness by activating PTGER1. Our results reveal a type of CCA self-driven progression dependent on bile exosomal miR-182/183-5p and MCs, which is a new interplay pattern of CCA and bile.
胆管癌（CCA）是一种起源于胆管的高度致命恶性肿瘤。目前的 CCA 诊断和预后评估不能满足临床需求。很少进行胆汁检测，在此，我们旨在通过评估胆汁外泌体浓度和成分来评估胆汁液体活检的临床意义。
通过透射电子显微镜、纳米颗粒跟踪分析和纳米流式细胞术鉴定和定量了 CCA、胰腺癌和胆总管结石患者的胆汁和血清中的外泌体。通过液相色谱串联质谱和 microRNA 测序（miRNA-seq）评估外泌体成分。不同疾病的胆汁外泌体浓度无显著差异，但 CCA 胆汁外泌体中 miR-182-5p 和 miR-183-5p 异常上调。CCA 组织和胆汁中高 miR-182/183-5p 提示预后不良。由 CCA 细胞分泌的胆汁外泌体 miR-182/183-5p 可被胆管上皮细胞或 CCA 细胞吸收。在人源化小鼠的异种移植中，我们表明，胆汁外泌体 miR-182/183-5p 通过靶向 CCA 细胞和肥大细胞（MCs）中的羟基前列腺素脱氢酶，增加前列腺素 E2 的产生，从而刺激 PTGER1 并增加 CCA 干性，从而促进 CCA 的增殖、侵袭和上皮-间充质转化（EMT）。在单细胞 mRNA-seq 中，羟基前列腺素脱氢酶主要在 MCs 中表达。miR-182/183-5p 通过增加 VEGF-A 的表达，促使 MC 从 MC 中释放 VEGF-A，从而促进血管生成。
CCA 细胞将外泌体 miR-182/183-5p 分泌到胆汁中，该外泌体靶向 CCA 细胞和 MC 中的羟基前列腺素脱氢酶，增加前列腺素 E2 和 VEGF-A 的释放。前列腺素 E2 通过激活 PTGER1 促进干性。我们的结果揭示了一种依赖于胆汁外泌体 miR-182/183-5p 和 MC 的 CCA 自驱动进展类型，这是 CCA 和胆汁之间的一种新的相互作用模式。
