Acquisition of lymph node, but not distant metastatic potentials, by the overexpression of CXCR4 in human oral squamous cell carcinoma
Acquisition of lymph node, but not distant metastatic potentials, by the overexpression of CXCR4 in human oral squamous cell carcinoma
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DOI：
10.1038/labinvest.3700190
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发表时间：
2004-12-01
影响因子：
5
通讯作者：
Sato, M
中科院分区：
文献类型：
--
作者：
Uchida, DE;Begum, NM;Sato, M
最近，已经表明趋化因子/受体相互作用决定了几种类型癌症中侵袭性肿瘤细胞的目的地。基质细胞衍生因子-1（SDF-1; CXCL 12）/CXCR 4系统可能参与口腔鳞癌的淋巴结转移。为了进一步阐明SDF-1/CXCR 4系统在口腔SCC中的作用，我们使用口腔SCC细胞产生CXCR 4稳定转染子（IH-CXCR 4），并将它们与不表达CXCR 4且在体内没有淋巴结转移潜力的IH进行比较。我们将增强型绿色荧光蛋白（GFP）融合CXCR 4导入IH细胞，在约60%的G418抗性细胞中检测到GFP荧光存在于细胞质和细胞膜中。这种批量转染表达了高水平的CXCR 4 mRNA和蛋白，并表现出特征性的钙通量和趋化活性与SDF-1治疗中观察到的。SDF-1在IH-CXCR 4细胞中双相激活细胞外信号调节激酶（ERK）1/2，但持续激活Akt/蛋白激酶B（PKB）。最重要的是，IH-CXCR 4细胞经常转移到颈部淋巴结，但在裸鼠原位接种中不转移到远处器官。此外，这些淋巴结转移抑制的有丝分裂原活化蛋白激酶/ERK激酶抑制剂，U 0126，或磷脂酰肌醇3激酶抑制剂，渥曼青霉素的治疗。这些结果表明，SDF-1/CXCR 4信号通路通过ERK 1/2或Akt/PKB通路介导口腔鳞癌淋巴结转移的建立。
Recently, it has been suggested that chemokine/receptor interactions determine the destination of the invasive tumor cells in several types of cancer. It has also been proposed that the stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system might be involved lymph node metastasis in oral squamous cell carcinoma (SCC). In order to further clarify the role of the SDF-1/CXCR4 system in oral SCC, we generated CXCR4 stable transfectants (IH-CXCR4) using oral SCC cells, and compared them to IH, which did not express CXCR4 and which did not have lymph node metastatic potentials in vivo. We introduced enhanced green fluorescent protein (GFP) fused-CXCR4 into IH cells, and detected the GFP fluorescence in the cytoplasm and cell membrane in approximately 60% of the G418-resistant cells. This bulk-transfectant expressed a high level of CXCR4 mRNA and protein, and exhibited the characteristic calcium fluxes and chemotactic activity observed in treatment with SDF-1. SDF-1 biphasically activated extracellular signal-regulated kinase (ERK)1/2, but continuously activated Akt/protein kinase B (PKB) in IH-CXCR4 cells. Most importantly, IH-CXCR4 cells frequently metastasized to the cervical lymph node, but not to the distant organs in the orthotopic inoculation of nude mice. Furthermore, these lymph node metastases were inhibited by the treatment of a mitogen-activated protein kinase/ERK kinase inhibitor, U0126, or a phosphatidylinositol 3 kinase inhibitor, wortmannin. These results indicate that SDF-1/CXCR4 signaling mediates the establishment of lymph node metastasis in oral SCC via ERK1/2 or Akt/PKB pathway.