Expression of the chemokine CXCL14 and cetuximab-dependent tumour suppression in head and neck squamous cell carcinoma.
Expression of the chemokine CXCL14 and cetuximab-dependent tumour suppression in head and neck squamous cell carcinoma.
复制标题
DOI：
10.1038/oncsis.2016.43
复制
发表时间：
2016-07-11
期刊：
影响因子：
6.2
通讯作者：
Hata RI
中科院分区：
文献类型：
--
作者：
Kondo T;Ozawa S;Ikoma T;Yang XY;Kanamori K;Suzuki K;Iwabuchi H;Maehata Y;Miyamoto C;Taguchi T;Kiyono T;Kubota E;Hata RI
西妥昔单抗是一种抗表皮生长因子受体（EGFR）的单克隆抗体，已成功用于治疗一些结直肠癌和头颈部鳞状细胞癌（HNSCC）患者。为了有效治疗，首先确定西妥昔单抗反应的患者是至关重要的。据报道，EGFR表达水平和/或EGFR通路下游信号分子突变的存在是结直肠癌患者中西妥昔单抗反应性的决定因素;然而，HNSCC患者中报告的数据有限。我们先前报道了趋化因子CXCL 14对异种移植的HNSCC细胞具有肿瘤抑制作用，异种移植的HNSCC细胞可分为两组，在血清饥饿培养条件下表达CXCL 14的细胞和不表达CXCL 14的细胞。在这里，我们采用表达CXCL 14的HSC-3细胞和不表达CXCL 14的YCU-H891细胞作为两组的代表，并比较它们对西妥昔单抗的反应和它们在各种条件下的CXCL 14表达。通过将西妥昔单抗注射到荷瘤小鼠中，抑制了由HSC-3细胞（其在体内和体外表达CXCL 14）引发的异种移植肿瘤的生长;然而，对于YCU-H891细胞，既没有观察到趋化因子的表达，也没有观察到异种移植肿瘤生长的西妥昔单抗依赖性抑制。这两种类型的细胞表达EGFR，并且没有一种类型的EGFR下游信号分子中存在突变，这在西妥昔单抗耐药的结肠癌患者中已有报道。细胞外信号调节激酶（ERK）信号的抑制增加HSC-3细胞中CXCL 14信使RNA（mRNA）的水平，但不增加YCU-H891细胞中CXCL 14信使RNA（mRNA）的水平。我们还观察到YCU-H891细胞中CXCL 14启动子区域高甲基化，用5-氮杂-2 ′-脱氧胞苷处理启动子去甲基化恢复CXCL 14 mRNA表达和体内西妥昔单抗介导的肿瘤生长抑制。最后，我们观察到在体内肿瘤生长抑制时，YCU-H891细胞被改造为表达CXCL 14异位在强力霉素的存在下。这些结果表明，CXCL 14表达可能是西妥昔单抗依赖性肿瘤抑制的良好预测生物标志物。
Cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR), has been successfully used to treat some patients with colorectal cancer and those with head and neck squamous cell carcinoma (HNSCC). For the effective treatment, it is essential to first identify cetuximab-responsive patients. The level of EGFR expression and/or the presence of mutations in signalling molecules downstream of the EGFR pathway have been reported to be determining factors for cetuximab responsiveness in colorectal cancer patients; however, limited data have been reported for HNSCC patients. We previously reported that the chemokine CXCL14 exhibits tumour-suppressive effects against xenografted HNSCC cells, which may be classified into two groups, CXCL14-expressing and non-expressing cells under serum-starved culture conditions. Here we employed CXCL14-expressing HSC-3 cells and CXCL14-non-expressing YCU-H891 cells as representatives of the two groups and compared their responses to cetuximab and their CXCL14 expression under various conditions. The growth of xenografted tumours initiated by HSC-3 cells, which expressed CXCL14 in vivo and in vitro, was suppressed by the injection of cetuximab into tumour-bearing mice; however, neither the expression of the chemokine nor the cetuximab-dependent suppression of xenograft tumour growth was observed for YCU-H891 cells. Both types of cells expressed EGFR and neither type harboured mutations in signalling molecules downstream of EGFR that have been reported in cetuximab-resistant colon cancer patients. The inhibition of the extracellular signal-regulated kinase (ERK) signalling increased the levels of CXCL14 messenger RNA (mRNA) in HSC-3 cells, but not in YCU-H891 cells. We also observed that the CXCL14 promoter region in YCU-H891 cells was hypermethylated, and that demethylation of the promoter by treatment with 5-aza-2′-deoxycytidine restored CXCL14 mRNA expression and in vivo cetuximab-mediated tumour growth suppression. Finally, we observed in vivo tumour growth suppression when YCU-H891 cells were engineered to express CXCL14 ectopically in the presence of doxycycline. These results indicate that CXCL14 expression may be a good predictive biomarker for cetuximab-dependent tumour suppression.