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Expression of CXCR4 and its down-regulation by IFN-gamma in head and neck squamous cell carcinoma
Akihiro Katayama1, Takeshi Ogino, Nobuyuki Bandoh
1Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical College, Asahikawa, Japan.
Purpose:
The functional expression of CXCR4, which plays roles in cell migration and proliferation in response to its unique ligand stromal cell-derived factor-1 (SDF-1), has been reported in variety of carcinomas. However, CXCR4 expression and its functional role in head and neck squamous cell carcinomas (HNSCC) remain unclear. In this study, we investigated CXCR4 expression and analyzed its functions in HNSCC cell lines. We also attempted to regulate CXCR4 expression using cytokines, such as interleukin-1beta, tumor necrosis factor-alpha, and IFN-gamma. Finally, we investigated correlation between CXCR4 expression and clinical features in patients with HNSCC.
Experimental Design:
Six HNSCC cell lines were used in this study. Reverse transcription-PCR and flow cytometry analysis were shown for CXCR4 expressions with or without stimulations of cytokines. SDF-1-mediated cell migration was assayed in Matrigel-coated chemotaxis chamber. The SDF-1-mediated cell proliferation was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The SDF-1-mediated signaling pathways were analyzed by Western blot analysis. Biopsy specimens from 56 patients with HNSCC were used for immunohistologic analysis.
Results:
The significant CXCR4 expression was found in HSQ-89, IMC-3, and Nakamura cells. The SDF-1-mediated cell migration and proliferation were observed in CXCR4-positive cells. SDF-1 also promoted rapid phosphorylation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways in CXCR4-positive cells. The SDF-1-mediated cell migration and proliferation of CXCR4-positive cells were inhibited by neutralization of CXCR4. Among three cytokines tested, IFN-gamma significantly reduced CXCR4 expression and SDF-1-induced cell migration and proliferation of CXCR4-positive cells. Immunohistologic analysis revealed that patients with advanced neck status and patients who developed distant metastases showed significantly higher CXCR4 expression, and the cause-specific survival of patients with CXCR4-expression was significantly shorter. Furthermore, multivariate analysis confirmed that CXCR4 positive was the independent factor for cause-specific death.
Conclusion:
Our results may provide an insight into future therapeutic agent that inhibits tumor metastasis and progression via down-regulating CXCR4 expression in patients with HNSCC.
Insights
CXCR4 (C-X-C chemokine receptor type 4) is highly expressed in head and neck squamous cell carcinomas (HNSCC), driving tumor cell migration and proliferation. Down-regulating CXCR4 may offer a therapeutic strategy for HNSCC metastasis.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- CXCR4 (C-X-C chemokine receptor type 4) and its ligand SDF-1 (stromal cell-derived factor-1) are implicated in various carcinomas.
- The role of CXCR4 in head and neck squamous cell carcinomas (HNSCC) is not well understood.
Purpose of the Study:
- To investigate CXCR4 expression and function in HNSCC cell lines.
- To explore the regulation of CXCR4 by cytokines (IL-1β, TNF-α, IFN-γ).
- To correlate CXCR4 expression with clinical features in HNSCC patients.
Main Methods:
- Analysis of CXCR4 expression in six HNSCC cell lines using RT-PCR and flow cytometry.
- Assays for SDF-1-mediated cell migration and proliferation.
- Western blot analysis of signaling pathways (ERK1/2, Akt).
- Immunohistologic analysis of 56 HNSCC patient biopsy specimens.
Main Results:
- Significant CXCR4 expression was detected in specific HNSCC cell lines.
- SDF-1 stimulation enhanced migration and proliferation in CXCR4-positive cells, activating ERK1/2 and Akt pathways.
- IFN-γ significantly reduced CXCR4 expression and SDF-1-induced cellular activities.
- High CXCR4 expression correlated with advanced neck status, distant metastasis, and shorter cause-specific survival in HNSCC patients.
- Multivariate analysis identified CXCR4 positivity as an independent predictor of cause-specific death.
Conclusions:
- CXCR4 plays a significant role in HNSCC progression and metastasis.
- Targeting CXCR4 may represent a potential therapeutic strategy for HNSCC.
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