外泌体膜联蛋白A2通过与Toll样受体2（TLR2）结合激活腹膜间皮细胞，促进卵巢癌腹膜转移。
Exosomal ANXA2 facilitates ovarian cancer peritoneal metastasis by activating peritoneal mesothelial cells through binding with TLR2.
作者信息
Zhang Jingni, Liu Hongmei, Wu Qiulei, Liu Tong, Liu Xiaoli, Cai Jing, Yi Xiaoqing, Wang Zehua, Gao Lingling
机构信息
Departmentof Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
出版信息
Cell Commun Signal. 2024 Dec 21;22(1):616. doi: 10.1186/s12964-024-01987-y.
BACKGROUND
Peritoneal dissemination of ovarian cancer (OvCa) can be largely attributed to the formation of a metastatic microenvironment driven by tumoral exosomes. Here, we aimed to elucidate the mechanisms through which exosomal annexin A2 (ANXA2) derived from OvCa cells induces an HPMC phenotypic shift in favour of peritoneal metastasis.
METHODS
Immunohistochemistry and orthotopic and intraperitoneal OvCa xenograft mouse models were used to clarify the relationship between tumour ANXA2 expression and peritoneal metastasis. Exosomes were isolated from OvCa cell lines via ultracentrifugation. Functional experiments on cell proliferation and motility, and western blot were performed to investigate the activation of HPMCs and its impact on tumour cell in vitro. High-throughput transcriptional sequencing and rescue experiments in which ANXA2 inhibitor (LCKLSL) or the toll-like receptor 2 (TLR2) inhibitor (C29) was used to co-culture the HPMCs with exosome were employed to identify the crucial functional molecules through which exosomal ANXA2 activates HPMCs. The impact of exosomal ANXA2-activated HPMCs on tumour progression was assessed via functional experiments.
RESULTS
Primary OvCa samples with high ANXA2 expression exhibited a stronger tendency to metastasize to the abdominal cavity. Tumoral ANXA2 promoted OvCa peritoneal metastasis through the secretion of exosomes carrying ANXA2. ANXA2-loaded exosomes activated HPMCs through exosomal ANXA2 binding to TLR2, shifting the phenotype of HPMCs towards mesenchymal cells, increasing their migration and invasion capacities, and elevating the expression of lipocalin 2 (LCN2). High LCN2 expression in HPMCs promoted OvCa cell adhesion, proliferation, motility, and lipid metabolism reprogramming.
CONCLUSION
Exosomal ANXA2 secreted by tumour cells activates HPMCs and induces the expression of LCN2, which in turn promotes the peritoneal metastasis of OvCa.
背景
卵巢癌（OvCa）的腹膜播散很大程度上归因于肿瘤外泌体驱动的转移性微环境的形成。在此，我们旨在阐明源自OvCa细胞的外泌体膜联蛋白A2（ANXA2）诱导人腹膜间皮细胞（HPMC）表型转变以利于腹膜转移的机制。
方法
采用免疫组织化学以及原位和腹腔内OvCa异种移植小鼠模型来阐明肿瘤ANXA2表达与腹膜转移之间的关系。通过超速离心从OvCa细胞系中分离外泌体。进行细胞增殖和运动功能实验以及蛋白质印迹法，以研究体外HPMCs的激活及其对肿瘤细胞的影响。采用高通量转录测序以及使用ANXA2抑制剂（LCKLSL）或Toll样受体2（TLR2）抑制剂（C29）将HPMCs与外泌体共培养的拯救实验，以鉴定外泌体ANXA2激活HPMCs的关键功能分子。通过功能实验评估外泌体ANXA2激活的HPMCs对肿瘤进展的影响。
结果
ANXA2高表达的原发性OvCa样本表现出更强的向腹腔转移的倾向。肿瘤ANXA2通过分泌携带ANXA2的外泌体促进OvCa腹膜转移。载有ANXA2的外泌体通过外泌体ANXA2与TLR2结合激活HPMCs，使HPMCs的表型向间充质细胞转变，增加其迁移和侵袭能力，并提高脂质运载蛋白2（LCN2）的表达。HPMCs中高LCN2表达促进OvCa细胞黏附、增殖、运动及脂质代谢重编程。
结论
肿瘤细胞分泌的外泌体ANXA2激活HPMCs并诱导LCN2表达，进而促进OvCa的腹膜转移。
Zotero 插件