CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway
CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway
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DOI：
10.1093/carcin/bgn108
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发表时间：
2008-08-01
期刊：
影响因子：
4.7
通讯作者：
Kuo, Min-Liang
中科院分区：
文献类型：
--
作者：
Tan, Ching-Ting;Chu, Chia-Yu;Kuo, Min-Liang
喉和下咽鳞状细胞癌(LHSCCs)是常见的头颈部肿瘤，具有较高的淋巴转移和肺转移倾向。在这里，我们报道了LHSCCs表达高水平的功能性CXCR4受体，这是趋化因子基质细胞衍生因子-1(SDF-1/CXCL12)的天然产物。LHSCC患者的原发肿瘤免疫组织化学显示CXCR4和CXCL12显著表达。CXCR4的高表达而不是CXCL12的高表达与LN和远处转移相关。逆转录聚合酶链式反应和免疫印迹结果表明，LHSCC细胞株也表达CXCR4信使RNA(MRNA)和蛋白，但未能检测到CXCL12mRNA的表达。CXCL12可增强LHSCC细胞外信号调节激酶(ERK)通路的激活，并可被CXCR4拮抗剂(AMD3100)和特异性MEK抑制剂(U0126)阻断。结果表明，CXCL12诱导Hep-2细胞基质金属蛋白酶(MMP13)的表达增加，但不影响MMP2和MMP9的表达。同样，U0126通过刺激CXCL12几乎抑制了Hep-2细胞中基质金属蛋白酶-13的诱导。转录因子c-jun是ERK途径的下游因子，在CXCL12作用10min后，转录因子c-jun很容易被磷酸化并移位到细胞核。C-jun反义寡核苷酸阻断c-jun活性可显著降低CXCL12诱导的基质金属蛋白酶-13表达和细胞侵袭能力。CXCL12可能通过旁分泌激活CXCR4，触发ERK/c-jun依赖的基质金属蛋白酶-13上调，从而增强LHSCC细胞的侵袭力。
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.