Excretory/secretory products of the carcinogenic liver fluke are endocytosed by human cholangiocytes and drive cell proliferation and IL6 production.
Excretory/secretory products of the carcinogenic liver fluke are endocytosed by human cholangiocytes and drive cell proliferation and IL6 production.
复制标题
致癌性肝氟的排泄/分泌产物由人胆管细胞内吞，并驱动细胞增殖和IL6产生。
DOI：
10.1016/j.ijpara.2015.06.001
复制
发表时间：
2015-10
影响因子：
4
通讯作者：
Sripa B
中科院分区：
文献类型：
--
作者：
Chaiyadet S;Smout M;Johnson M;Whitchurch C;Turnbull L;Kaewkes S;Sotillo J;Loukas A;Sripa B
由猫尾后睾吸虫引起的肝吸虫感染仍然是亚洲许多地区的主要公共卫生问题，包括泰国、老挝人民民主共和国、越南和柬埔寨，其中胆管癌（CCA -胆管上皮肝癌）的发病率非常高。在其他因素中，O.胆汁上皮细胞分泌的猫尿排泄/分泌产物（OvES）被认为是慢性炎症和胆管细胞增殖的原因，但细胞内化OvES的机制仍不清楚。在此，我们孵育正常人胆管细胞（H69），人胆管癌细胞（KKU-100，KKU-M156）和人结肠癌细胞（Caco-2）与OvES和分析不同的内吞抑制剂的影响，以解决ES蛋白的细胞摄取的机制。OvES优先被肝细胞系内化，并且被H69细胞最有效/快速地内化。没有证据表明ES蛋白被运输到胆管细胞器，并且大部分荧光在细胞质中被检测到。用网格蛋白抑制剂预处理显著降低OvES产物的摄取，特别是H69细胞的摄取。OvES诱导肝细胞（H69和CCA系）增殖，但不诱导肠细胞（Caco-2）增殖，并且使用经典内吞途径（网格蛋白和小窝）的抑制剂阻断增殖。OvES驱动H69细胞而不是Caco-2细胞分泌IL 6，细胞因子分泌被内吞抑制剂显著降低。这是第一个已知的研究，以解决寄生虫ES蛋白的宿主上皮细胞的内吞作用，并揭示了这种寄生虫导致东南亚最具破坏性的癌症之一的途径。
Liver fluke infection caused by Opisthorchis viverrini remains a major public health problem in many parts of Asia including Thailand, Lao PDR, Vietnam and Cambodia, where there is a strikingly high incidence of cholangiocarcinoma (CCA - hepatic cancer of the bile duct epithelium). Among other factors, uptake of O. viverrini excretory/secretory products (OvES) by biliary epithelial cells has been postulated to be responsible for chronic inflammation and proliferation of cholangiocytes, but the mechanisms by which cells internalize OvES are still unknown. Herein we incubated normal human cholangiocytes (H69), human cholangiocarcinoma cells (KKU-100, KKU-M156) and human colon cancer (Caco-2) cells with OvES and analysed the effects of different endocytic inhibitors to address the mechanism of cellular uptake of ES proteins. OvES was internalized preferentially by liver cell lines, and most efficiently/rapidly by H69 cells. There was no evidence for trafficking of ES proteins to cholangiocyte organelles, and most of the fluorescence was detected in the cytoplasm. Pretreatment with clathrin inhibitors significantly reduced the uptake of OvES products, particularly by H69 cells. OvES induced proliferation of liver cells (H69 and CCA lines) but not intestinal (Caco-2) cells, and proliferation was blocked using inhibitors of the classical endocytic pathways (clathrin and caveolae). OvES drove IL6 secretion by H69 cells but not Caco-2 cells, and cytokine secretion was significantly reduced by endocytosis inhibitors. This the first known study to address the endocytosis of helminth ES proteins by host epithelial cells and sheds light on the pathways by which this parasite causes one of the most devastating forms of cancer in south-eastern Asia.