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外泌体中的肝激酶 B1 抑制免疫检查点程序性死亡配体 1 和肝内胆管癌的转移进展。

Liver kinase B1 in exosomes inhibits immune checkpoint programmed death ligand 1 and metastatic progression of intrahepatic cholangiocarcinoma.

机构信息

Third Department of General Surgery, The Central Hospital of Xiangtan, Xiangtan, Hunan 411100, P.R. China.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, D‑30159 Hannover, Germany.

出版信息

Oncol Rep. 2022 Sep;48(3). doi: 10.3892/or.2022.8367. Epub 2022 Jul 20.

DOI:10.3892/or.2022.8367
PMID:35856436
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9350976/
Abstract

The increasing morbidity and high mortality of intrahepatic cholangiocarcinoma (ICC) has led to the urgent need for new diagnostics and therapeutics. Liver kinase B1 (LKB1) exerts a tumor suppressor role in multiple malignances, while its regulatory role in exosomes secreted by ICC cells is obscure. In the present study, exosomes were extracted from cell culture supernatants of RBE and HCCC‑9810 ICC cells as well as plasma of patients with ICC by ultracentrifugation and the morphology of exosomes was identified by transmission electron microscopy. Notably, compared with that of intracellular LKB1, the protein level of exosomal LKB1 was decreased. Silencing intracellular LKB1 increased the protein levels of programmed death ligand 1 (PD‑L1), Slug and phosphorylated‑AKT in exosomes, accompanied by decreased expression levels of exosomal LKB1. Exosomes with lower protein levels of LKB1 promoted the expression of the immune checkpoint PD‑L1, malignant phenotypes of ICC cells , and cancer metastasis . Moreover, the low level of exosomal LKB1 in plasma was tightly associated with the poor prognosis of patients with ICC. Collectively, exosomal LKB1 inhibits the immune checkpoint PD‑L1 and metastasis of ICC cells. These findings may provide new methods for the diagnosis and immune therapy of ICC.

摘要

肝内胆管癌（ICC）发病率和死亡率的不断上升，导致对新的诊断和治疗方法的迫切需求。肝激酶 B1（LKB1）在多种恶性肿瘤中发挥肿瘤抑制作用，但其在 ICC 细胞分泌的外泌体中的调节作用尚不清楚。在本研究中，通过超速离心从 RBE 和 HCCC-9810 ICC 细胞的细胞培养上清液以及 ICC 患者的血浆中提取外泌体，并通过透射电子显微镜鉴定外泌体的形态。值得注意的是，与细胞内 LKB1 相比，外泌体 LKB1 的蛋白水平降低。沉默细胞内 LKB1 增加了外泌体中程序性死亡配体 1（PD-L1）、Slug 和磷酸化-AKT 的蛋白水平，同时降低了外泌体 LKB1 的表达水平。LKB1 蛋白水平较低的外泌体促进了免疫检查点 PD-L1、ICC 细胞恶性表型和癌症转移的表达。此外，血浆中外泌体 LKB1 水平低与 ICC 患者预后不良密切相关。总之，外泌体 LKB1 抑制 ICC 细胞的免疫检查点 PD-L1 和转移。这些发现可能为 ICC 的诊断和免疫治疗提供新方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10d9/9350976/8401d86b9dfd/or-48-03-08367-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10d9/9350976/9e201a4c0549/or-48-03-08367-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10d9/9350976/075ea8f8b3eb/or-48-03-08367-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10d9/9350976/ab217017dd0d/or-48-03-08367-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10d9/9350976/57ee80a46287/or-48-03-08367-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10d9/9350976/8401d86b9dfd/or-48-03-08367-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10d9/9350976/9e201a4c0549/or-48-03-08367-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10d9/9350976/075ea8f8b3eb/or-48-03-08367-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10d9/9350976/ab217017dd0d/or-48-03-08367-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10d9/9350976/57ee80a46287/or-48-03-08367-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10d9/9350976/8401d86b9dfd/or-48-03-08367-g04.jpg

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