Chemokine receptor 7 enhances cell chemotaxis and migration of metastatic squamous cell carcinoma of head and neck through activation of matrix metalloproteinase-9

Abstract

The mechanisms leading to squamous cell carcinoma of head and neck (SCCHN) metastasis are not fully understood. Although evidence shows that the chemokine receptor 7 (CCR7) and its ligand CCL19 may regulate tumor dissemination, their role is not clearly defined in SCCHN. Matrix metalloproteinases break consisting of tissue barrier to the surrounding tissue invasion and metastasis by destroying the balance of matrix degradation of the basement membrane of tumor cells and extracellular matrix (ECM). We used chemotaxis and migration assays, western blotting, gelatin zymography, actin polymerization assay, immunofluorescence staining and immunohistochemical analysis to explore whether MMP-9 can be activated by CCL19 (CCR7's ligand) and its role in SCCHN. The experiments were performed in the metastatic SCCHN cell line PCI-37B after pre-incubation of the cells with CCL19 and SB-3CT (inhibitor of MMP-9). Our results demonstrated that CCR7 favors PCI-37B cell chemotaxis and migration, upregulation of MMP-9 protein and motivates the activity of MMP-9 protein, induces reorganization of the actin cytoskeleton and upregulation of MMP-9 protein. SB-3CT can block all these effects. Collectively, our data indicated that CCR7 regulates cell chemotaxis and migration via MMP-9 in metastatic SCCHN, and these results provide a basis for new strategies in preventing metastases of SCCHN.

Significance of chemokine and chemokine receptors in head and neck squamous cell carcinoma: A critical review

“…Additionally, CCL21 is a potent stimuli for SCC migration [27]. Accordingly, CCL21 receptor -CCR7 -induces cytoskeleton modifications which in turn stimulate tumor cell migration, invasion, adhesion and survival of HNSCC cells via activation of PI3K/AKT and MAPK's and MMP-9 release [30,[32][33][34].…”

“…In the context of oral cancer, it was previously shown that expression of CXCL8, CXCL6 (a CXCL8 homologue) and CXCR2 in tumor samples correlates with lymph node " CCL2 " ROS " proliferation, " invasion " tumor growth [19] HNSCC " invasion, " macrophage infiltration " angiogenesis [20] HNSCC and OSCC cell lines " CCL2 ; patient survival " CCL2 " ERK/AKT/STAT3 phosphorilation " survival in vitro [21] " CCL2 " EMT via AKT [ OSCC, and OSCC cell line " CCR7 " lymph node metastasis " stage " tumor size" CCL21/CCR7 " invasion " adhesion to lymph nodes in vitro [27] HNSCC, HNSCC cell lines and mice " CCL19 " lymph node metastasis CCR7 blockade ; AKT ; BCL-2 ; tumor growth [28] HNSCC and HNSCC cell lines " CCR7 " lymph node metastasis " adhesive ability [29] HNSCC and HNSCC cell lines " CCR7 " lymph node metastasis " CCR7 " migration " adhesion and cytoskeleton reorganization [30] " CCR7/CCL19 " PKCa " NF-KB " CCR7 " PKCa " stage " lymph node metastasis [31] " CCR7/CCL19 " PI3K " CDC42 and actin polymerization [32] " CCR7 " migration " MMP-9 " b1 integrin " cytoskeleton reorganization [33] " CCR7/CCL19 " ERK/JNK ; E-cadherin " vimentin " invasion [34] CCL20 (LARC, Exodus-1 and MIP3-a)…”

CXCL7 promotes proliferation and invasion of cholangiocarcinoma cells

“…Chemokines, secreted by various cell types, play central roles in chemotaxis (5,6). According to the order of conserved cysteine residues, chemokines are classified into C, CC, CXC and C(X)3C, and CXC chemokines are further classified into ELR + CXC and ELR-CXC, according to the absence or presence of the amino-terminal ELR motif (6,7).…”

Expression of chemokine receptor CCR7 is a negative prognostic factor for patients with gastric cancer: a meta-analysis

“…Cancer cells with upregulated CCR7 disseminate from the primary tumor presumably by sensing the immobilized CCL21 gradient and actively migrate toward the next lymphatic vessel and the T-cell zone of lymph nodes. In addition to contributing to tumor cell survival by activating the phosphatidylinositol-3-kinase/Akt signaling pathway [29], the CCL21/CCR7 axis can upregulate matrix metalloproteinase 9 [30], E-cadherin, Slug, vimentin, and N-cadherin [31], which are considered as markers of epithelial-mesenchymal transition (EMT); that is to say, CCR7 can stimulate cancer cells to acquire an EMT phenotype. Accumulating evidence has shown that the EMT is a pathological process contributing to cancer progression, particularly cancer invasion, dissemination, and metastasis [32].…”