Abstract
Oral squamous cell carcinoma (OSCC) is an aggressive tumor that has a poor prognosis, with high levels of local invasion and lymph node metastasis. Vascular endothelial growth factor A (VEGF-A) plays essential roles in OSCC tumor angiogenesis and metastasis. Monocyte chemoattractant protein-1 (MCP-1, CCL2) is implicated in various inflammatory conditions and pathological processes, including oral cancer. The existing evidence has failed to confirm any correlation between MCP-1 or VEGF-A expression and OSCC angiogenesis. In this study, high expression levels of MCP-1 and VEGF-A were positively correlated with disease stage in patients with OSCC. In oral cancer cells, MCP-1 increased VEGF-A expression and subsequently promoted angiogenesis; miR-29c mimic reversed MCP-1 activity. We also found that MCP-1 modulated VEGF-A expression and angiogenesis through CCR2/ILK/MEK1/2 signaling. Ex vivo results of the chick embryo chorioallantoic membrane (CAM) assay revealed the angiogenic qualities of MCP-1, with increased numbers of visible blood vessel branches. Our data suggest that MCP-1 is a new molecular therapeutic target for the inhibition of angiogenesis and metastasis in OSCC.
Highlights
Oral squamous cell carcinoma (OSCC) is an aggressive oral epithelial neoplasm that has a low overall 5-year survival rate of 50–60% [1], largely because of the development of metastasis [2]
We demonstrate that MCP-1 promotes Vascular endothelial growth factor A (VEGF-A) expression in OSCC by activating integrin-linked kinase (ILK) and MEK1/2 signaling and downregulating miR-29c expression, all of which subsequently enhances vascular endothelial growth factor (VEGF)-A-induced tumor angiogenesis
Previous research has demonstrated that VEGF-A and angiopoietin 2 (ANGPT2) are critical players in tumor angiogenesis, while VEGF-A has been considered the primary factor driving the expansion of the tumor angiogenesis [22, 23]
Summary
Oral squamous cell carcinoma (OSCC) is an aggressive oral epithelial neoplasm that has a low overall 5-year survival rate of 50–60% [1], largely because of the development of metastasis [2]. OSCC metastasis is a complex process that is largely driven by angiogenesis [4, 5]. Few therapeutic options are available for OSCC patients with metastatic disease [4]. MCP-1 can accelerate breast cancer metastasis by promoting angiogenesis in a vascular endothelial growth factor (VEGF)-A-dependent manner [8]. Some evidence suggests that MCP-1 might be involved in the development of OSCC [4, 9], including inducing changes in epithelial-mesenchymal transition (EMT) markers via paracrine or autocrine signaling [3], but the exact mechanism remains unclear
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