MiR-744 functions as a proto-oncogene in nasopharyngeal carcinoma progression and metastasis via transcriptional control of ARHGAP5.
MiR-744 functions as a proto-oncogene in nasopharyngeal carcinoma progression and metastasis via transcriptional control of ARHGAP5.
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miR-744通过ARHGAP5的转录控制在鼻咽癌进展和转移中充当原癌基因。
DOI：
10.18632/oncotarget.3754
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发表时间：
2015-05-30
期刊：
影响因子：
--
通讯作者：
Song W
中科院分区：
文献类型：
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作者：
Fang Y;Zhu X;Wang J;Li N;Li D;Sakib N;Sha Z;Song W
鼻咽癌是一种高侵袭性、易转移的上皮性癌。鼻咽癌复发和转移缺乏有效的治疗策略是鼻咽癌生存率停滞不前的主要原因。因此，迫切需要了解鼻咽癌进展的分子机制，寻找新的靶向治疗途径。近来发现，microRNAs是潜在的促肿瘤或抑制肿瘤的因子，参与肿瘤的发生。在本研究中，我们发现miR-744在鼻咽癌组织中的表达高于鼻咽上皮组织，并且miR-744的上调与鼻咽癌的TNM分期、肿瘤的发生和转移密切相关。功能研究表明miR-744在鼻咽癌中是一个新的肿瘤促进剂。此外，我们确定miR-744通过直接与其启动子相互作用，从而在转录水平上调节其表达，从而针对促肿瘤基因ARHGAP5(Rho GTPase激活蛋白5)。ARHGAP5的重新导入类似于miR-744的作用，而沉默ARHGAP5明显阻断了miR-744诱导的细胞迁移和侵袭的增强。ARHGAP5的高表达与miR-744、鼻咽癌分期、淋巴结转移呈正相关。综上所述，这些数据首次揭示了miR-744通过直接靶向ARHGAP5启动子而发挥其原癌功能。这一新发现的miR-744/ARHGAP5通路为进一步了解鼻咽癌的进展和转移提供了新的研究方向，并为鼻咽癌的治疗提供了新的靶点。
Nasopharyngeal carcinoma (NPC) is a highly invasive and metastasis-prone epithelial cancer. The paucity of effective treatment strategies for recurrent and metastatic NPC is the major cause for stagnating survival rate of NPC. Therefore, it's urgent to understand the molecular mechanisms underlying NPC progression and identify novel avenues for targeted therapy. It has emerged recently that microRNAs are potential pro-tumorigenic or tumor-suppressive factors that participate in oncogenesis. In this study, we found that miR-744 expression was upregulated in NPC specimens compared to nasopharyngeal epithelium (NPE) tissue, and miR- 744 upregulation was significantly associated with TNM stage, tumorigenesis and metastasis. Functional studies revealed that miR-744 acts as a novel tumor promotor in NPC. Moreover, we determined that miR-744 targets ARHGAP5 (Rho GTPase activating protein 5), a protumorigenic gene, by directly interacting with its promoter and thereby regulating its expression at transcriptional level. Reintroduction of ARHGAP5 resembled the effects of miR-744 and silencing of ARHGAP5 clearly abrogated miR-744-induced enhancement of cell migration and invasion. High level of ARHGAP5 was positively correlated with that of miR-744 and with advanced stages of NPC, as well as with lymph node metastasis. Taken together, these data reveal for the first time that miR-744 exerts its proto-oncogenic function by directly targeting ARHGAP5 promoter. This newly identified miR-744/ARHGAP5 pathway provides further insight into the progression and metastasis of NPC and indicates potential novel therapeutic targets for NPC.