RAB37 Hypermethylation Regulates Metastasis and Resistance to Docetaxel-Based Induction Chemotherapy in Nasopharyngeal Carcinoma
RAB37 Hypermethylation Regulates Metastasis and Resistance to Docetaxel-Based Induction Chemotherapy in Nasopharyngeal Carcinoma
复制标题
RAB37 高甲基化调节鼻咽癌的转移和对多西紫杉醇诱导化疗的耐药性
DOI：
10.1158/1078-0432.ccr-18-0532
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发表时间：
2018-12-15
影响因子：
11.5
通讯作者：
Liu, Na
中科院分区：
文献类型：
--
作者：
Li, Yingqin;Yang, Xiaojing;Liu, Na
目的：表观遗传学改变通过基因调控在肿瘤转移和耐药中发挥重要作用。然而，表观遗传学改变在鼻咽癌（NPC）转移中的功能特征和分子机制仍不清楚。实验设计：利用基因调控网络分析技术，对正常组织和鼻咽癌组织中的转移特异性失调基因进行鉴定，并在已发表的Gene-Expression Omnibus数据集中验证其表达。在鼻咽癌中检测RAB 37下调的调节和功能作用，并在体外和体内验证，并探索RAB 37的下游靶点。评价RAB 37甲基化在鼻咽癌转移和化疗敏感性中的临床价值。结果：我们确定RAB 37是一个特异性的高甲基化基因，在NPC中最常见的下调。此外，RAB 37下调归因于其启动子的高甲基化，并与NPC中的转移和多西他赛化疗耐药相关特征显著相关。异位RAB 37过表达抑制鼻咽癌细胞转移并增强对多西他赛的化疗敏感性。机制上，RAB 37与TIMP 2共定位，调节TIMP 2分泌，抑制下游MMP 2活性，从而改变NPC细胞转移。此外，RAB 37高甲基化与NPC患者的不良临床结局相关。我们开发了一种基于RAB 37甲基化和N分期的预后模型，该模型有效地预测了NPC患者远处转移的风险增加和对含紫杉醇的诱导化疗（IC）的有利反应。结论：这项研究表明，RAB 37高甲基化参与NPC转移和化疗耐药，我们的预后模型可以识别远处转移风险高的患者，并可能从多西他赛IC中获益。
Purpose: 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. Experimental Design: 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 RAB37 downregulation was examined in NPC and was validated in vitro and in vivo, and downstream target of RAB37 was explored. The clinical value of RAB37 methylation was evaluated in NPC metastasis and chemosensitivity. Results: We identified RAB37 as a specific hypermethylated gene that is most commonly downregulated in NPC. Moreover, RAB37 downregulation was attributed to hypermethylation of its promoter and was significantly associated with metastasis- and docetaxel chemoresistance-related features in NPC. Ectopic RAB37 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, RAB37 hypermethylation was correlated with poor clinical outcomes in patients with NPC. We developed a prognostic model based on RAB37 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. Conclusions: This study shows that RAB37 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.