CCL18 promotes the invasion and metastasis of breast cancer through Annexin A2
CCL18 promotes the invasion and metastasis of breast cancer through Annexin A2
复制标题
CCL18通过Annexin A2促进乳腺癌侵袭和转移
DOI：
10.3892/or.2019.7426
复制
发表时间：
2020-02-01
期刊：
影响因子：
4.2
通讯作者：
Zhang, Baogang
中科院分区：
文献类型：
--
作者：
Zhao, Chunling;Zheng, Shuxian;Zhang, Baogang
趋化因子（C-C基序）配体18（CCL 18）来源于乳腺肿瘤相关巨噬细胞（TAM），其主要是具有M2表型的巨噬细胞亚群。CCL 18与其受体PYK 2 N-末端结构域相互作用受体1（Nir 1）结合，并通过PI 3 K/Akt/GSK 3 β/Snail信号通路诱导乳腺癌细胞中的上皮-间质转化（EMT）促进肿瘤进展和转移。近年来的研究表明，膜联蛋白A2（Annexin A2，AnxA 2）在乳腺癌的侵袭、转移、血管生成、增殖、肌动蛋白聚合及化疗耐药等方面发挥重要作用。本研究旨在阐明CCL 18通过AnxA 2促进乳腺癌进展的分子机制，这些机制尚未完全了解。Western blot分析显示AnxA 2在高侵袭性乳腺癌细胞系和浸润性导管癌中表达上调。此外，通过趋化性、划痕、Matrigel侵袭和自发转移试验，证明AnxA 2增强了乳腺癌细胞的侵袭和人乳腺癌细胞向CCL 18刺激的SCID小鼠肺的转移。细胞F-肌动蛋白测量试验表明，AnxA 2的减少通过乳腺癌细胞中整合素β 1的磷酸化来抑制CCL 18诱导的F-肌动蛋白聚合。免疫荧光和western blot分析显示AnxA 2通过PI 3 K/Akt/GSK 3 beta/Snail信号通路促进CCL 18诱导的EMT，LY 294002抑制AnxA 2的磷酸化。总之，AnxA 2作为Nir 1与CCL 18结合的下游分子，通过PI 3 K/Akt/GSK 3 β/Snail信号通路促进乳腺癌中EMT的侵袭和转移。这项研究表明，AnxA 2是一个潜在的抗乳腺癌侵袭/转移的治疗干预的目标。
Chemokine (C-C motif) ligand 18 (CCL18) is derived from breast tumor-associated macrophages (TAMs), which are primarily a macrophage subpopulation with an M2 phenotype. CCL18 binds to its receptor, PYK2 N-terminal domain interacting receptor 1 (Nir1), and promotes tumor progression and metastasis by inducing epithelial-mesenchymal transition (EMT) via the PI3K/Akt/GSK3 beta/Snail signaling pathway in breast cancer cells. Recent research shows that Annexin A2 (AnxA2) plays a significant role in the invasion, metastasis, angiogenesis, proliferation, F-actin polymerization and multidrug resistance to chemotherapy of breast cancer. The present study aimed to elucidate the molecular mechanisms by which CCL18 promotes breast cancer progression through AnxA2 which are not fully understood. Western blot analysis showed that the expression of AnxA2 was upregulated in highly invasive breast cancer cell lines and invasive ductal carcinoma. Furthermore, through chemotaxis, scratch, Matrigel invasion, and spontaneous metastasis assays, it was demonstrated that AnxA2 enhanced the invasion of breast cancer cells and the metastasis of human breast cancer cells to lungs of SCID mice with CCL18 stimulation. Cellular F-actin measurement assay showed that reduction of AnxA2 suppressed CCL18-induced F-actin polymerization though phosphorylation of integrin beta 1 in breast cancer cells. Immunofluorescence and western blot analysis revealed that AnxA2 promoted CCL18-induced EMT via the PI3K/Akt/GSK3 beta/Snail signaling pathway, and LY294002 inhibited the phosphorylation of AnxA2 in vitro. In brief, AnxA2, as a downstream molecule of Nir 1 binding to CCL18, promotes invasion and metastasis by EMT through the PI3K/Akt/GSK3 beta/Snail signaling pathway in breast cancer. This study suggests that AnxA2 is a potential anti-invasion/metastasis target for therapeutic intervention in breast cancer.