Tan Ching-Ting, Chu Chia-Yu, Lu Ying-Chang, Chang Cheng-Chi, Lin Been-Ren, Wu Hsaio-Hui, Liu Hsin-Ling, Cha Shih-Ting, Prakash Ekambaranellore, Ko Jenq-Yuh, Kuo Min-Liang
Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei 100, Taiwan.
Carcinogenesis. 2008 Aug;29(8):1519-27. doi: 10.1093/carcin/bgn108. Epub 2008 May 16.
Laryngeal and hypopharyngeal squamous cell carcinomas (LHSCCs) are common head and neck cancers with a high propensity for lymph node (LN) and lung metastasis. Here, we report that LHSCCs express high levels of functional CXCR4 receptors, native for chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). Primary tumor immunohistochemistry from LHSCC patients has revealed significant expression of CXCR4 and CXCL12. Greater expression of CXCR4 but not that of CXCL12 is correlated with LN and distant metastasis. Reverse transcription-polymerase chain reaction and western blots have demonstrated that CXCR4 messenger RNA (mRNA) and protein were expressed in LHSCC cell lines as well, but failed to detect CXCL12 mRNA expression. CXCL12 treatment enhanced extracellular signal-regulated kinase (ERK) pathway activation and the motility/invasiveness of LHSCC cell lines, which were blocked by treatment with a CXCR4 antagonist (AMD3100) and a specific MEK inhibitor (U0126). Results show that the mRNA and protein levels of matrix metalloproteinase (MMP)-13, but not MMP-2 or MMP-9, were elevated in HEp-2 cells in response to CXCL12. Again, U0126 almost inhibited the induction of MMP-13 in HEp-2 cells by stimulating CXCL12. The transcriptional factor, c-Jun, a downstream factor of ERK pathway, was found to be readily phosphorylated and translocated to the nucleus after 10 min of exposure to CXCL12. Blockage of c-Jun activity by transfection with c-jun antisense oligodeoxynucleotide significantly decreased CXCL12-induced MMP-13 expression and cell invasion. CXCL12 seems to enhance LHSCC cell invasion through paracrine-activated CXCR4, which triggers ERK/c-Jun-dependent MMP-13 upregulation.
喉和下咽鳞状细胞癌（LHSCC）是常见的头颈部癌症，极易发生淋巴结（LN）转移和肺转移。在此，我们报告LHSCC表达高水平的功能性CXCR4受体，该受体对趋化因子基质细胞衍生因子-1（SDF-1/CXCL12）具有天然亲和力。LHSCC患者的原发性肿瘤免疫组织化学显示CXCR4和CXCL12有显著表达。CXCR4的高表达而非CXCL12的高表达与LN转移和远处转移相关。逆转录-聚合酶链反应和蛋白质印迹表明，CXCR4信使核糖核酸（mRNA）和蛋白质也在LHSCC细胞系中表达，但未检测到CXCL12 mRNA表达。CXCL12处理增强了细胞外信号调节激酶（ERK）途径的激活以及LHSCC细胞系的运动性/侵袭性，而用CXCR4拮抗剂（AMD3100）和特异性MEK抑制剂（U0126）处理可阻断这些作用。结果显示，响应CXCL12时，HEp-2细胞中基质金属蛋白酶（MMP）-13的mRNA和蛋白质水平升高，而MMP-2或MMP-9未升高。同样，U0126几乎抑制了CXCL12刺激HEp-2细胞中MMP-13的诱导。转录因子c-Jun是ERK途径的下游因子，发现在暴露于CXCL12 10分钟后很容易被磷酸化并转移至细胞核。用c-jun反义寡脱氧核苷酸转染阻断c-Jun活性可显著降低CXCL12诱导的MMP-13表达和细胞侵袭。CXCL12似乎通过旁分泌激活CXCR4增强LHSCC细胞侵袭，这触发了ERK/c-Jun依赖性MMP-13上调。
