This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Katayama, A. Articles by Harabuchi, Y. Search for Related Content PubMed PubMed Citation Articles by Katayama, A. Articles by Harabuchi, Y.

Expression of CXCR4 and Its Down-Regulation by IFN- in Head and Neck Squamous Cell Carcinoma

Authors' Affiliation: Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical College, Asahikawa, Japan

Requests for reprints: Yasuaki Harabuchi, Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido 078-8510, Japan. Phone: +81-166-68-2554; Fax: +81-166-68-2559; E-mail: hyasu{at}asahikawa-med.ac.jp.

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-1ß, tumor necrosis factor-, and IFN-. 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- 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.

Key Words: CXCR4 • IFN- • migration • proliferation • prognostic factor

This article has been cited by other articles:

				A. O. Rehman and C.-Y. Wang SDF-1{alpha} Promotes Invasion of Head and Neck Squamous Cell Carcinoma by Activating NF-{kappa}B J. Biol. Chem., July 18, 2008; 283(29): 19888 - 19894. [Abstract] [Full Text] [PDF]

				J. Meijer, J. Ogink, B. Kreike, D. Nuyten, K. E. de Visser, and E. Roos The Chemokine Receptor CXCR6 and Its Ligand CXCL16 Are Expressed in Carcinomas and Inhibit Proliferation Cancer Res., June 15, 2008; 68(12): 4701 - 4708. [Abstract] [Full Text] [PDF]

				I. Kryczek, S. Wei, E. Keller, R. Liu, and W. Zou Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis Am J Physiol Cell Physiol, March 1, 2007; 292(3): C987 - C995. [Abstract] [Full Text] [PDF]

				S. Ohira, M. Sasaki, K. Harada, Y. Sato, Y. Zen, K. Isse, K. Kozaka, A. Ishikawa, K. Oda, Y. Nimura, et al. Possible Regulation of Migration of Intrahepatic Cholangiocarcinoma Cells by Interaction of CXCR4 Expressed in Carcinoma Cells with Tumor Necrosis Factor-{alpha} and Stromal-Derived Factor-1 Released in Stroma Am. J. Pathol., April 1, 2006; 168(4): 1155 - 1168. [Abstract] [Full Text] [PDF]