Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, China.
Clin Cancer Res. 2018 Dec 15;24(24):6495-6508. doi: 10.1158/1078-0432.CCR-18-0532. Epub 2018 Aug 21.
Epigenetic alterations play important roles in metastasis and drug resistance through gene regulation. However, the functional features and molecular mechanisms of epigenetic changes remain largely unclear in nasopharyngeal carcinoma (NPC) metastasis.
Gene regulatory network analysis was used to identify metastatic-specific dysregulated genes between normal and NPC tissues and the expression was validated in published Gene-Expression Omnibus data set. The regulatory and functional role of downregulation was examined in NPC and was validated and , and downstream target of was explored. The clinical value of methylation was evaluated in NPC metastasis and chemosensitivity.
We identified as a specific hypermethylated gene that is most commonly downregulated in NPC. Moreover, downregulation was attributed to hypermethylation of its promoter and was significantly associated with metastasis- and docetaxel chemoresistance-related features in NPC. Ectopic overexpression suppressed NPC cell metastasis and enhanced chemosensitivity to docetaxel. Mechanistically, RAB37 colocalized with TIMP2, regulated TIMP2 secretion, inhibited downstream MMP2 activity, and consequently altered NPC cell metastasis. Furthermore, hypermethylation was correlated with poor clinical outcomes in patients with NPC. We developed a prognostic model based on methylation and N stage that effectively predicted an increased risk of distant metastasis and a favorable response to docetaxel-containing induction chemotherapy (IC) in NPC patients.
This study shows that hypermethylation is involved in NPC metastasis and chemoresistance, and that our prognostic model can identify patients who are at a high risk of distant metastasis and might benefit from for docetaxel IC.
表观遗传改变通过基因调控在转移和耐药中发挥重要作用。然而，在鼻咽癌（NPC）转移中，表观遗传变化的功能特征和分子机制在很大程度上仍不清楚。
使用基因调控网络分析来鉴定正常和 NPC 组织之间具有转移特异性的失调基因，并在已发表的基因表达综合数据库中验证表达。在 NPC 中检验下调的调节和功能作用，并进行验证和下游靶基因的探索。评估在 NPC 转移和化学敏感性中的甲基化的临床价值。
我们确定了作为一个特异性高甲基化基因，在 NPC 中最常见下调。此外，下调归因于其启动子的高甲基化，与 NPC 转移和多西紫杉醇化疗耐药相关特征显著相关。异位过表达抑制 NPC 细胞转移并增强对多西紫杉醇的化疗敏感性。在机制上，RAB37 与 TIMP2 共定位，调节 TIMP2 分泌，抑制下游 MMP2 活性，从而改变 NPC 细胞转移。此外，在 NPC 患者中，甲基化与不良临床结局相关。我们基于甲基化和 N 分期开发了一个预后模型，该模型可有效预测 NPC 患者远处转移的风险增加和对多西紫杉醇含诱导化疗（IC）的良好反应。
这项研究表明，甲基化参与 NPC 转移和化疗耐药，我们的预后模型可以识别出远处转移风险较高的患者，并可能受益于多西紫杉醇 IC。
