Vesnarinone downregulates CXCR4 expression via upregulation of Kruppel-like factor 2 in oral cancer cells
Vesnarinone downregulates CXCR4 expression via upregulation of Kruppel-like factor 2 in oral cancer cells
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DOI：
10.1186/1476-4598-8-62
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发表时间：
2009-08-12
期刊：
影响因子：
37.3
通讯作者：
Miyamoto, Youji
中科院分区：
文献类型：
--
作者：
Uchida, Daisuke;Onoue, Tomitaro;Miyamoto, Youji
背景：我们已证实基质细胞衍生因子-1(SDF-1；CXCL12)/CXCR4系统参与口腔鳞癌(SCC)淋巴结转移的发生。化疗是治疗包括口腔鳞癌在内的口腔癌的有力手段，但化疗药物对CXCR4表达的影响尚不清楚。结果：用3种不同的化疗药物：5-氟尿嘧啶、顺铂和维斯利酮(3，4-dihydro-6-[4-(3，4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone)在B88细胞中检测了CXCR4的表达，B88细胞具有高水平的CXCR4和淋巴结转移潜能。在我们研究的3种化疗药物中，只有维司力农在mRNA和蛋白水平上下调了CXCR4的表达。维司纳酮显著抑制荷瘤裸鼠的淋巴转移。此外，维斯力农显著抑制了2.7kb的人CXCR4启动子的活性，我们鉴定了转录因子Kruppel-like factor2(KLF2)是一个新的维司力农反应分子，它与CXCR4启动子结合在相对于转录起始点的-300到-167位。KLF2的强制表达导致CXCR4基因表达下调，CXCR4启动子活性降低。使用针对KLF2的siRNA导致CXCR4mRNA上调。结论：维司力农通过上调KLF2下调CXCR4在口腔癌中的表达。
Background: 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; 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.Results: The 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, Kruppel-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.Conclusion: These Results indicate that vesnarinone downregulates CXCR4 via the upregulation of KLF2 in oral cancer.