Abstract
BackgroundWe have demonstrated that the stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system is involved in the establishment of lymph node metastasis in oral squamous cell carcinoma (SCC). Chemotherapy is a powerful tool for the treatment of oral cancer, including oral SCC; however, the effects of chemotherapeutic agents on the expression of CXCR4 are unknown. In this study, we examined the expression of CXCR4 associated with the chemotherapeutic agents in oral cancer cells.ResultsThe expression of CXCR4 was examined using 3 different chemotherapeutic agents; 5-fluorouracil, cisplatin, and vesnarinone (3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2-(1H)-quinolinone) in B88, a line of oral cancer cells that exhibits high levels of CXCR4 and lymph node metastatic potential. Of the 3 chemotherapeutic agents that we examined, only vesnarinone downregulated the expression of CXCR4 at the mRNA as well as the protein level. Vesnarinone significantly inhibited lymph node metastasis in tumor-bearing nude mice. Moreover, vesnarinone markedly inhibited 2.7-kb human CXCR4 promoter activity, and we identified the transcription factor, Krüppel-like factor 2 (KLF2), as a novel vesnarinone-responsive molecule, which was bound to the CXCR4 promoter at positions -300 to -167 relative to the transcription start site. The forced-expression of KLF2 led to the downregulation of CXCR4 mRNA and impaired CXCR4 promoter activity. The use of siRNA against KLF2 led to an upregulation of CXCR4 mRNA.ConclusionThese Results indicate that vesnarinone downregulates CXCR4 via the upregulation of KLF2 in oral cancer.
Highlights
We have demonstrated that the stromal cell-derived factor-1 (SDF-1; CXCL12)/ CXCR4 system is involved in the establishment of lymph node metastasis in oral squamous cell carcinoma (SCC)
We have demonstrated that lymph node metastatic oral squamous cell carcinoma (OSCC) cells express functional CXCR4, and the SDF-1/ CXCR4 system is involved in lymph node metastatic processes in OSCC [13,14]
Expression of CXCR4 induced by the chemotherapeutic agents In complete medium or DMSO, the expression of CXCR4 mRNA was transiently downregulated after the medium was changed, but mRNA expression was gradually upregulated and recovered to the basal level at 24 h (Figure 2a)
Summary
We have demonstrated that the stromal cell-derived factor-1 (SDF-1; CXCL12)/ CXCR4 system is involved in the establishment of lymph node metastasis in oral squamous cell carcinoma (SCC). Chemotherapy is a powerful tool for the treatment of oral cancer, including oral SCC; the effects of chemotherapeutic agents on the expression of CXCR4 are unknown. We examined the expression of CXCR4 associated with the chemotherapeutic agents in oral cancer cells. Oral cancers, including OSCC are characterized by a high degree of local invasion and a high rate of metastases to the cervical lymph nodes. Lymph node metastasis is frequently detected upon the first visit to a hospital, but it appears during initial treatments that include radiotherapy and chemotherapy. Despite the evidence accumulated to date, there is no known molecular target for anti-metastatic therapy against nodal involvement patients with oral cancer
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