Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Cancer Res. 2011 Jan 1;71(1):225-33. doi: 10.1158/0008-5472.CAN-10-1850.
Several microRNAs (miRNA) have been implicated in nasopharyngeal carcinoma (NPC), a highly invasive and metastatic cancer that is widely prevalent in southern China. In this study, we report that microRNA miR-26a is commonly downregulated in NPC specimens and NPC cell lines with important functional consequences. Ectopic expression of miR-26a dramatically suppressed cell proliferation and colony formation by inducing G(1)-phase cell-cycle arrest. We found that miR-26a strongly reduced the expression of EZH2 oncogene in NPC cells. Similar to the restoring miR-26 expression, EZH2 downregulation inhibited cell growth and cell-cycle progression, whereas EZH2 overexpression rescued the suppressive effect of miR-26a. Mechanistic investigations revealed that miR-26a suppressed the expression of c-myc, the cyclin D3 and E2, and the cyclin-dependent kinase CDK4 and CDK6 while enhancing the expression of CDK inhibitors p14(ARF) and p21(CIP1) in an EZH2-dependent manner. Interestingly, cyclin D2 was regulated by miR-26a but not by EZH2, revealing cyclin D2 as another direct yet mechanistically distinct target of miR-26a. In clinical specimens, EZH2 was widely overexpressed and its mRNA levels were inversely correlated with miR-26a expression. Taken together, our results indicate that miR-26a functions as a growth-suppressive miRNA in NPC, and that its suppressive effects are mediated chiefly by repressing EZH2 expression.
几种 microRNAs（miRNA）已被牵连到鼻咽癌（NPC）中，这是一种在华南地区广泛流行的高度侵袭性和转移性癌症。在这项研究中，我们报告了 microRNA miR-26a 在 NPC 标本和 NPC 细胞系中普遍下调，并具有重要的功能后果。miR-26a 的异位表达通过诱导 G1 期细胞周期停滞，显著抑制了细胞增殖和集落形成。我们发现 miR-26a 在 NPC 细胞中强烈降低了 EZH2 癌基因的表达。类似于恢复 miR-26 的表达，EZH2 的下调抑制了细胞生长和细胞周期进程，而 EZH2 的过表达挽救了 miR-26a 的抑制作用。机制研究表明，miR-26a 以 EZH2 依赖的方式抑制了 c-myc、cyclin D3 和 E2、细胞周期蛋白依赖性激酶 CDK4 和 CDK6 的表达，同时增强了 CDK 抑制剂 p14(ARF)和 p21(CIP1)的表达。有趣的是，cyclin D2 受 miR-26a 调节但不受 EZH2 调节，表明 cyclin D2 是 miR-26a 的另一个直接但机制上不同的靶标。在临床标本中，EZH2 广泛过表达，其 mRNA 水平与 miR-26a 的表达呈负相关。总之，我们的结果表明，miR-26a 在 NPC 中作为生长抑制性 miRNA 发挥作用，其抑制作用主要通过抑制 EZH2 的表达来介导。
