CCL18 promotes the invasion and metastasis of breast cancer through Annexin A2

Zhao,Chunling; Zheng,Shuxian; Yan,Ziqian; Deng,Zikun; Wang,Ruige; Zhang,Baogang

doi:10.3892/or.2019.7426

CCL18 promotes the invasion and metastasis of breast cancer through Annexin A2

Authors:
- Chunling Zhao
- Shuxian Zheng
- Ziqian Yan
- Zikun Deng
- Ruige Wang
- Baogang Zhang
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Affiliations: Department of Cell Biology, Weifang Medical University, Weifang, Shandong 261053, P.R. China, Department of Pathology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
Published online on: December 11, 2019 https://doi.org/10.3892/or.2019.7426
Pages: 571-580

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Abstract

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/GSK3β/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 β1 in breast cancer cells. Immunofluorescence and western blot analysis revealed that AnxA2 promoted CCL18‑induced EMT via the PI3K/Akt/GSK3β/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/GSK3β/Snail signaling pathway in breast cancer. This study suggests that AnxA2 is a potential anti‑invasion/metastasis target for therapeutic intervention in breast cancer.

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