Abstract
The inflammatory chemokine (C–C motif) ligand 4 (CCL4) plays an important role in the pathogenesis and progression of cancer. In particular, higher serum CCL4 levels in patients with oral squamous cell carcinoma (OSCC) are associated with a more advanced stage of disease. OSCC accounts for approximately 95% of oral cancer in Taiwan and has a poor prognosis, due to aggressive local invasion and metastasis, leading to recurrence. OSCC spreads preferentially through lymphatic vessels and has the propensity to metastasize to the cervical lymph nodes even in the early stage of disease. Vascular endothelial growth factor C (VEGF-C) is an essential regulator of lymphangiogenesis. In particular, VEGF-C is specific to lymphatic vessel development, and VEGF-C expression levels have been found to directly correlate with lymph node metastasis in OSCC. However, it is unclear as to whether CCL4 correlates with VEGF-C expression and lymphangiogenesis in OSCC. We found that CCL4 increased VEGF-C expression and promoted lymphangiogenesis in oral cancer cells in vitro and in vivo. miR-195-3p mimic reversed CCL4-enhanced VEGF-C expression. CCL4 stimulation of oral cancer cells augmented JAK2 and STAT3 phosphorylation. Thus, CCL4 may be a new molecular therapeutic target for inhibition of lymphangiogenesis and metastasis in OSCC.
Highlights
Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the head and neck (~95%) in Taiwan, accounting for the fourth highest incidence of cancers in the male population and the first cause of death among 40-year-old Taiwanese men [1]
We thought that CCL4 might have an important role in oral cancer progression and lymph node revealed a positive correlation between serum Vascular endothelial growth factor C (VEGF-C) and CCL4 (Pearson’s correlation coefficient, R2 = 0.6) and (E) a positive correlation between VEGF-C and mRNA expression (Spearman’s rank correlation coefficient, R2 = 0.6)
As with previous research showing that lymphatic endothelial cells (LECs) proliferation, migration and tube formation generates new lymphatic vessels essential for tumor lymphangiogenesis [8], we found that incubating LECs for 24 h with conditioned medium (CM) from CCL4treated oral squamous cell carcinoma (OSCC) cells dramatically promoted LEC tube formation and migration (Figures 2C,D)
Summary
Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the head and neck (~95%) in Taiwan, accounting for the fourth highest incidence of cancers in the male population and the first cause of death among 40-year-old Taiwanese men [1]. As many as 50% or more of Taiwanese patients with OSCC present with stage III or stage IV at diagnosis, leading to a low overall 5-year survival rate [2]. This emphasizes the need to detect OSCC as early as possible and identify the mechanisms driving tumor lymphangiogenesis to improve survival. This study set out to determine the role of CCL4 in OSCC
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