Nakayama Ryuji, Arikawa Kazumune, Bhawal Ujjal K
Department of Preventive and Public Oral Health, Nihon University School of Dentistry at Matsudo, 2-870-1 Sakae-cho Nishi, Matsudo, Chiba 271-8587, Japan.
Research Institute of Oral Health, Nihon University School of Dentistry at Matsudo, 2-870-1 Sakae-cho Nishi, Matsudo, Chiba 271-8587, Japan.
J Cancer. 2017 Aug 25;8(15):3014-3027. doi: 10.7150/jca.21169. eCollection 2017.
Chemokines selectively attract and activate leukocytes and play roles in a variety of homeostatic and disease processes. Explore the biological properties of CXCL14 seems complicated due to unknown functional characteristics of CXCL14 in cancer. To study the multistep process of oral cancer development, we analyzed oral samples spanning normalcy, dysplasia and cancer from multiple perspectives, revealing a cascade of progressive changes. CXCL14 protein was expressed in the cytoplasm adjacent to tumors. T classification (P<0.001), clinical stage (P=0.0013) and nodal metastasis (P=0.0035) were significantly associated with CXCL14 in relationships between CXCL14 expression levels and tumor and patient characteristics. Compared with non-tumor tissue, expression of the epidermal growth factor receptor (EGFR) gene was increased in dysplasia and was further sustained in cancer. Our data show an inverse relationship between CXCL14 and EGFR expression levels in tumor cells indicating that CXCL14 expression is beneficial for tumor suppression. To explore epigenetic regulation and the impact of CXCL14 on oral cancer, analysis of CpG islands methylation in the promoter region indicated that the abnormal hypermethylation of that promoter region in tumor cells and tissues is one of the mechanisms causing the reduced expression. Restoration of CXCL14 expression was induced by treatment with 5-aza-2'-deoxycytidine. Using mouse models, we demonstrate that the restoration of CXCL14 expression in irradiation-induced oral carcinoma cells induces the expression of Late Cornified Envelope (LCE) genes. Our data suggest that LCE genes are a novel target of CXCL14 and are likely to have a tumor suppressor function through the modulation of CXCL14 expression. In conclusion, CXCL14 might play a pivotal role in the pathobiology of oral cancer, probably by regulating DNA methylation and leukocyte migration. The level of CXCL14 expression may be a valuable adjuvant parameter to predict the prognosis of patients with oral carcinoma and may be a potential therapeutic target.
趋化因子可选择性地吸引并激活白细胞，在多种体内平衡和疾病过程中发挥作用。由于CXCL14在癌症中的功能特性尚不清楚，探索其生物学特性似乎很复杂。为了研究口腔癌发生的多步骤过程，我们从多个角度分析了涵盖正常、发育异常和癌症的口腔样本，揭示了一系列渐进性变化。CXCL14蛋白在肿瘤邻近的细胞质中表达。在CXCL14表达水平与肿瘤及患者特征的关系中，T分类（P<0.001）、临床分期（P=0.0013）和淋巴结转移（P=0.0035）与CXCL14显著相关。与非肿瘤组织相比，表皮生长因子受体（EGFR）基因在发育异常中表达增加，并在癌症中进一步持续表达。我们的数据显示肿瘤细胞中CXCL14与EGFR表达水平呈负相关，表明CXCL14表达有利于肿瘤抑制。为了探索CXCL14对口腔癌的表观遗传调控及其影响，对启动子区域的CpG岛甲基化分析表明，肿瘤细胞和组织中该启动子区域的异常高甲基化是导致表达降低的机制之一。用5-氮杂-2'-脱氧胞苷处理可诱导CXCL14表达的恢复。使用小鼠模型，我们证明辐射诱导的口腔癌细胞中CXCL14表达的恢复可诱导晚期角质化包膜（LCE）基因的表达。我们的数据表明LCE基因是CXCL14的新靶点，可能通过调节CXCL14表达具有肿瘤抑制功能。总之，CXCL14可能在口腔癌的病理生物学中起关键作用，可能是通过调节DNA甲基化和白细胞迁移。CXCL14的表达水平可能是预测口腔癌患者预后的有价值的辅助参数，并且可能是潜在的治疗靶点。
