The essential roles of CCR7 in epithelial-to-mesenchymal transition induced by hypoxia in epithelial ovarian carcinomas

Abstract

The chemokine receptor CCR7 and its ligands CCL19/21 mediate the tumor mobility, invasion, and metastasis (Wu et al. Curr Pharm Des. 15:742-57, 2009). Hypoxia induced epithelial-to-mesenchymal transition (EMT) to facilitate the tumor biology. Here, we addressed the roles of CCR7 in epithelial ovarian carcinoma tissues and hypoxia-induced serous papillary cystic adenocarcinoma (SKOV-3) EMT. The expression level of CCR7 protein was analyzed by immunohistochemistry in 30 specimens of epithelial ovarian carcinomas. Western blot was used to investigate the expression of hypoxia-induced CCR7, HIF-1α, and EMT markers (N-cadherin, Snail, MMP-9). In addition, wound healing and Transwell assay were introduced to observe the capacity of migration and invasiveness. Our data showed CCR7 expression was observed in 22 cases of tissues and closely associated with lymph node metastasis and FIGO stage (III + IV). At 6, 12, 24, and 36 h following hypoxia, CCR7 and HIF-1α proteins were both obviously upregulated in a time-dependent method, compared with normal oxygen. In vitro, SKOV-3 expressed N-cadherin, Snail, and MMP-9 once either CCL21 stimulation or hypoxia induction, while hypoxia accompanied with CCL21 induction exhibited strongest upregulation of N-cadherin, Snail, and MMP-9 proteins. Besides, wound healing and Transwell assay further identified that hypoxia with CCL21 stimulation can remarkably promote cell migration and invasiveness. Taken together, CCR7 can constitutively express in epithelial ovarian carcinomas and be induced rapidly in response to hypoxia, which indeed participates in EMT development and prompts the cell migration and invasion. Thus, this study suggested that the epithelial ovarian cancer invasion and metastasis can be inhibited by antagonizing CCR7.

Crk-like adapter protein regulates CCL19/CCR7-mediated epithelial-to-mesenchymal transition via ERK signaling pathway in epithelial ovarian carcinomas

“…Based on all mentioned above, our team assumed that CrkL plays a potential role in the CCL19/ CCR7 signaling pathway in EOC development. Previously, we found CCR7 can constitutively express in epithelial ovarian carcinomas (EOC) and be induced rapidly in response to hypoxia, which indeed participates in EMT development and prompts the cell migration and invasion [20]. In the present study, we knocked down the CrkL protein in SKOV-3 cells to observe the effects of CrkL on CCR7-induced EMT.…”

Epithelial-to-Mesenchymal Transition in the Female Reproductive Tract: From Normal Functioning to Disease Pathology

“…Chemokine receptor CCR7 expression is induced rapidly in OC cells in response to hypoxia, and participates in EMT induction, cell migration and invasion. Hypoxia synergizes with CCL21, the CCR7 ligand, to induce a strong upregulation of N-cadherin, Snail, and MMP-9 proteins (244). …”

Therapeutic Lymphoid Organogenesis in the Tumor Microenvironment

“…For example, signaling via the CCL21/CCR7 axis has been shown to promote angiogenesis in inflammatory microenvironments (Pickens et al, 2012), and new blood vessel formation is one mechanism that facilitates both tumor growth and metastasis. In ovarian cancer, hypoxia induced an increase in intrinsic CCR7 expression by tumor cells, with CCL21 signaling in the hypoxic TME contributing to an upregulation of N-cadherin and the matrix metalloproteinase MMP-9, that are known to promote cell migration and invasiveness (Cheng et al, 2014). In patients with non-small cell lung cancer (NSCLC), a similar effect has been observed, as expression of MMP-1 and ADAM metallopeptidase with thrombospondin type 1 motif, 2 (ADAMTS2) in PBMCs was correlated with poor clinical outcome (Kossenkov et al, 2012).…”

“…Treatment of human gastric cancer cells with CCL19 induced the expression of MMP-9 and decreased levels of E-cadherin, consistent with a shift towards a pro-metastatic phenotype (Cheng, Guo, Yang, & Yang, 2015). In ovarian cancer, CCR7 + tumor status was also correlated with advanced disease stage and with lymph node metastasis, and these clinical parameters were linked to increased expression of MMP-9 and N-cadherin (Cheng et al, 2014) that were subsequently determined to be dependent upon CCL19 signaling (Cheng et al, 2015). …”