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, 510060, Guangzhou, Guangdong, China.
Cell Death Differ. 2019 Jun;26(6):1089-1106. doi: 10.1038/s41418-018-0208-2. Epub 2018 Oct 23.
Human nasopharyngeal carcinoma (NPC) has the highest metastatic rate in head and neck. However, the mechanisms underlying NPC metastasis remain unclear. Here using propensity-score-matched miRNA microarray analysis, miR-142-3p is identified to be the most correlated with distant-metastasis-free survival and downregulated in paraffin-embedded NPC with distant metastasis, which is validated in both internal cohort and external GEO dataset from Canada. miR-142 locus hypermethylation was observed and found to be associated with miR-142-3p downregulation in metastatic NPC. Furthermore, miR-142-3p was epigenetically silenced by EZH2-recruited DNMT1 and suppressed NPC cell metastasis and EMT. Intersecting PCR array gene profiling with bioinformatic prediction, we identify ZEB2 as a direct and functional target of miR-142-3p in NPC. Reversal of miR-142-3p silencing efficiently suppresses NPC cell invasion and metastasis. Moreover, epigenetic miR-142 hypermethylation is correlated with unfavorable prognosis in both training and validation cohorts. This study identifies miR-142-3p as a key suppressive regulator in NPC metastasis and reveals a DNMT1-mediated epigenetic mechanism for miR-142-3p silencing, providing a potential prognostic marker and therapeutic target to combat NPC metastasis.
人鼻咽癌（NPC）具有头颈癌中最高的转移率。然而，NPC 转移的机制仍不清楚。在这里，我们通过倾向评分匹配的 miRNA 微阵列分析，发现 miR-142-3p 与无远处转移生存最相关，并在有远处转移的 NPC 的石蜡包埋样本中下调，这在内部队列和加拿大的外部 GEO 数据集都得到了验证。观察到 miR-142 基因座的高甲基化，并发现与转移性 NPC 中的 miR-142-3p 下调有关。此外，miR-142-3p 被 EZH2 募集的 DNMT1 表观遗传沉默，并抑制 NPC 细胞转移和 EMT。与生物信息学预测相交的 PCR 阵列基因谱分析，我们确定 ZEB2 是 NPC 中 miR-142-3p 的直接和功能靶标。逆转 miR-142-3p 的沉默可有效抑制 NPC 细胞的侵袭和转移。此外，在训练和验证队列中，表观遗传 miR-142 高甲基化与不良预后相关。这项研究确定了 miR-142-3p 是 NPC 转移的关键抑制调节因子，并揭示了一种 DNMT1 介导的 miR-142-3p 沉默的表观遗传机制，为 NPC 转移提供了一个潜在的预后标志物和治疗靶点。
