Oral squamous cell carcinoma (OSCC), the sixth most common malignancy worldwide, has a poor prognosis due to its aggressiveness and potential for metastasis. Activation of monocyte chemoattractant protein-1 (MCP-1) and its receptor, CC chemokine receptor 2 (CCR2), induces angiogenic activation of endothelial cells, inflammatory responses and aberrant MCP-1/CCR2 expression in malignant tissues. However, the effect of MCP-1 and CCR2 in OSCC angiogenesis is unclear. Our study sought to determine how the MCP-1/CCR2 axis mediates VEGF-A expression in OSCC and results in angiogenesis. Immunohistochemistry (IHC) analysis identified higher concentrations of VEGF-A protein expression in tissue obtained from patients with OSCC compared with tissue from healthy controls; the degree of VEGF-A tumor expression was significantly associated with the clinical disease stage. Our in vitro investigations found that MCP-1 dose-dependently regulated VEGF-A expression through the CCR2, ILK and MEK signal transduction pathways. Following MCP-1 application, conditioned medium from the human OSCC cell line SCC4 significantly promoted endothelial progenitor cell (EPC) migration and tube formation; these events were attenuated and VEGF-A production was suppressed when we stimulated the OSCC cells with the pathway inhibitors RS102895, KP392, and PD98059. We also showed that microRNA (miR)-29c expression was negatively regulated by MCP-1 via the CCR2/ILK/MEK cascade, tying in with an analysis of the cancer genome atlas (TCGA) database showing lower levels of miR-29c expression in tissues from patients with oral cancer compared with samples from healthy controls. According to our results, the MCP-1/CCR2 axis promotes VEGF-A expression in OSCC via the ILK and MEK signal transduction pathways and downregulates miR-29c expression. Thus, MCP-1/CCR2 mediation of VEGF-A mobilizes EPCs required for OSCC and is important for tumor angiogenesis. MCP-1/CCR2 may be an appropriate target in the treatment of OSCC angiogenesis.

Citation Format: Ming-Yu Lien, Chih-Hsin Tang. The MCP-1/CCR2 axis enhances VEGF-A-dependent angiogenesis by directly downregulating miR-29c expression in oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 200.