Abstract
Crosstalk between tumor infiltrating macrophages and tumor cells is thought to play an indispensable role in oral squamous cell carcinomas (OSCC) by induction and maintenance of tolerance microenvironment. High infiltration of M2 macrophages and increasing expression of Kinesin family member 4A (Kif4A) in primary OSCC have been proved to correlate with greater tumoral size and poor clinical outcome. However, linkage between Kif4A and infiltrating macrophages in tumorigenesis and progression remains unclear. In the present study, we show that, the interaction between THP-1derived macrophage and OSCC cell line Cal-27 may up-regulate the Kif4A expression in both of them. Additionally, elevated soluble CCL2 in medium and more expression of CCR2 on macrophage were observed during the crosstalk. SiRNA of Kif4A and neutralizing antibody of CCL2 were utilized to identify that; increasing Kif4A can promote the recruitment of macrophages towards Cal-27 and educate them to M2 polarized macrophages via regulating CCL2/CCR2. In combination, the results of the present study may provide interesting clues to understanding the Kif4A-CCL2/CCR2-macrophage axis as a novel therapeutic target to improve the clinical outcome of OSCC.
Highlights
Oral squamous cell carcinoma (OSCC), being a major part of head and neck squamous cell carcinoma (HNSCC), accounts for almost 90% of all oral malignancies[1, 2]
To assess the expression and function of Kinesin family member 4A (Kif4A) in oral squamous cell carcinomas (OSCC) and mimic the crosstalk between macrophages and OSCC cells in the tumor microenvironment, we employed an in vitro two-chamber transwell co-culture system that allows the interaction between infiltrating macrophages and OSCC cells in the existence or absence of Kif4A silencing
Our results demonstrate that Kif4A of macrophages will be significantly up-regulated during co-culturing with OSCC cells; it may involve in specific activation of the CCR2 of macrophages
Summary
Oral squamous cell carcinoma (OSCC), being a major part of head and neck squamous cell carcinoma (HNSCC), accounts for almost 90% of all oral malignancies[1, 2]. As a kind of high-plastic immunocyte, macrophages constitute a major component of leukocytes in almost all types of malignancy including OSCC It responds to the stimulator in varied tumor microenvironments and be polarized with the release of a far-ranging of cytokines, chemokines and enzymes that mediate cancer cells invasion into surrounding normal tissues, and metastasis to local or distant sites[5]. It has been reported that Kif4A has close association with activation of immunocyte[13], and our former microarray study has found a decreased expression of CCL2 and CCR2 in mouse’s macrophage cell line when Kif4A is silencing (unpublished) It is absent or present at very low level in most adult normal tissues, cDNA microarray study and histochemical analysis reveal that there is an over-expression of Kif4A mRNA in human cervical cancer and it might be a prognostic biomarker and a possible therapeutic target for lung cancer[14, 15]. The aim of resent study is to assess whether Kif4A might recruit macrophage and modulate it towards an immune tolerance feature by CCL2-signaling in OSCC
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