Abstract
Chemokine (C-C motif) ligand 18 (CCL18) has been implicated in the pathogenesis and progression of various cancers; however, in oral squamous cell carcinoma (OSCC), the role of CCL18 is unknown. In this study, we found that CCL18 was overexpressed in primary OSCC tissues and was associated with an advanced clinical stage. CCL18 was found in both the cytoplasm and cell membrane of OSCC cells and was predominantly produced by cancer epithelial cells, as opposed to tumor-infiltrating macrophages. In vitro studies indicated that the effects of endogenous CCL18 on OSCC cell growth, migration, and invasion could be blocked by treatment with a neutralizing anti-CCL18 antibody or CCL18 knockdown, while exogenous recombinant CCL18 (rCCL18) rescued those effects. Akt was activated in rCCL18-treated OSCC cells, while LY294002, a pan-PI3K inhibitor, abolished both endogenous and exogenous CCL18-induced OSCC cell invasion. In vivo, LY294002 treatment attenuated rCCL18-induced OSCC cell growth. Our results indicate that CCL18 acts in an autocrine manner via Akt activation to stimulate OSCC cell growth and invasion during OSCC progression. They also provide a potential therapeutic target for the treatment of oral cancer.
Highlights
Oral squamous cell carcinoma (OSCC) accounts for approximately 90% of oral malignancies, with a 5-year survival rate of less than 50%, despite improved methods for diagnosis and therapy [1, 2]
Our findings demonstrate that elevated autocrine CCL18 accelerates cancer cell growth and invasion via Akt activation in oral squamous cell carcinoma (OSCC)
We identified a positive association between CCL18 expression and tumor TNM stage in OSCC patients (P = 0.040, Table 1)
Summary
Oral squamous cell carcinoma (OSCC) accounts for approximately 90% of oral malignancies, with a 5-year survival rate of less than 50%, despite improved methods for diagnosis and therapy [1, 2]. Cancer cell growth and invasion are critical processes during OSCC development [3, 4]. Chemokines, a large family of cytokines that bind to specific G-protein-coupled receptors, participate in cancer development by activating downstream signaling pathways and affecting cellular behaviors [5,6,7]. Chemokine (C-C motif) ligand 18 (CCL18), a member of the CC chemokine subset, plays a crucial role in immune processes and inflammation by triggering biological responses in dendritic cells, fibroblasts, monocytes/macrophages, and cancer cells [8,9,10]. The origin of CCL18 may be cancer-type specific, because prostate cancer epithelial cells secrete CCL18 [15]. CCL18 could act in an autocrine manner, paracrine manner, or both, during cancer development
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