Restoration of BRAK/CXCL14 gene expression by gefitinib is associated with antitumor efficacy of the drug in head and neck squamous cell carcinoma
Restoration of BRAK/CXCL14 gene expression by gefitinib is associated with antitumor efficacy of the drug in head and neck squamous cell carcinoma
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DOI：
10.1111/j.1349-7006.2009.01281.x
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发表时间：
2009-11-01
期刊：
影响因子：
5.7
通讯作者：
Hata, Ryu-Ichiro
中科院分区：
文献类型：
--
作者：
Ozawa, Shigeyuki;Kato, Yasumasa;Hata, Ryu-Ichiro
吉非替尼（ZD 1839，易瑞沙）是一种表皮生长因子（EGF）受体酪氨酸激酶特异性抑制剂，其临床疗效已在具有EGF受体突变的非小细胞肺癌患者中显示，因此这些突变是发现药物应答者的有用标志物。最近的研究表明，表皮生长因子受体基因突变是罕见的鳞状细胞癌在食管和头颈部地区。我们以前报道过，表皮生长因子治疗可下调头颈部鳞状细胞癌（HNSCC）细胞中趋化因子BRAK/CXCL 14的表达，并且肿瘤细胞中BRAK的强制表达可降低异种移植物中细胞的致瘤性。因此，我们研究了通过吉非替尼恢复BRAK表达与该药物抑制肿瘤的功效之间的关系。我们发现EGF通过MEK-细胞外信号调节激酶途径下调BRAKE表达，并且这种下调的表达在体外被吉非替尼恢复。口服吉非替尼显著（P < 0.001）降低了三种HNSCC细胞系（HSC-2、HSC-3和HSC-4）异种移植物在雌性无胸腺裸鼠中的肿瘤生长，伴随着肿瘤组织中BRAK表达的特异性增加。在BRAKE非表达细胞的情况下未观察到药物的这种肿瘤抑制作用。此外，BRAK shRNA载体的引入降低了HSC-3细胞中BRAK的表达水平和吉非替尼的体内抗肿瘤功效。我们的数据显示肿瘤细胞中BRAK表达水平与肿瘤生长速率之间的反比关系，表明吉非替尼诱导的BRAK表达增加有利于体内肿瘤抑制。（Cancer Sci 2009）。
Clinical efficacy of gefitinib (ZD1839, Iressa), which is an inhibitor specific for epidermal growth factor (EGF) receptor tyrosine kinase, has been shown in non-small-cell lung carcinoma patients with EGF receptor mutations, so these mutations are useful marker(s) to find a responder for the drug. Recent studies have shown that the EGF receptor gene mutation is rare in squamous cell carcinoma in the esophageal and head and neck regions. We previously reported that the expression of the chemokine BRAK/CXCL14 in head and neck squamous cell carcinoma (HNSCC) cells was down-regulated by EGF treatment, and that forced expression of BRAK in tumor cells decreased the tumorigenicity of the cells in xenografts. Thus, we investigated the relationship between restoration of BRAK expression by gefitinib and the efficacy of the drug for tumor suppression. We found that EGF down-regulated BRAK expression through the MEK-extracellular signal regulated kinase pathway and that this down-regulated expression was restored by gefitinib in vitro. Oral administration of gefitinib significantly (P < 0.001) reduced tumor growth of xenografts of three HNSCC cell lines (HSC-2, HSC-3, and HSC-4), in female athymic nude mice, accompanied by an increase in BRAK expression specifically in tumor tissue. This tumor-suppressing effect of the drug was not observed in the case of BRAK non-expressing cells. Furthermore introduction of BRAK shRNA vector reduced both the expression levels of BRAK in HSC-3 cells and the antitumor efficacy of gefitinib in vivo. Our data showing an inverse relationship between BRAK expression levels in tumor cells and the tumor growth rate indicate that the gefitinib-induced increase in BRAK expression is beneficial for tumor suppression in vivo. (Cancer Sci 2009).