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微小RNA-744通过对ARHGAP5的转录调控在鼻咽癌进展和转移中发挥原癌基因的作用。

MiR-744 functions as a proto-oncogene in nasopharyngeal carcinoma progression and metastasis via transcriptional control of ARHGAP5.

作者信息

Fang Yuan, Zhu Xiaoxia, Wang Jian, Li Na, Li Dianhe, Sakib Nazmus, Sha Zhou, Song Wen

机构信息

Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

出版信息

Oncotarget. 2015 May 30;6(15):13164-75. doi: 10.18632/oncotarget.3754.

Abstract

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.

摘要

鼻咽癌(NPC)是一种具有高度侵袭性且易于转移的上皮性癌症。复发性和转移性鼻咽癌缺乏有效的治疗策略,这是导致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,并确定靶向治疗的新途径。最近发现,微小RNA是参与肿瘤发生的潜在促肿瘤或抑肿瘤因子。在本研究中,我们发现与鼻咽上皮(NPE)组织相比,miR-744在鼻咽癌标本中的表达上调,并且miR-744上调与TNM分期、肿瘤发生和转移显著相关。功能研究表明,miR-744在鼻咽癌中作为一种新的肿瘤促进因子发挥作用。此外,我们确定miR-744通过直接与其启动子相互作用,从而在转录水平调节其表达,靶向ARHGAP5(Rho GTPase激活蛋白5)这一促肿瘤基因。重新引入ARHGAP5类似于miR-744的作用,而沉默ARHGAP5明显消除了miR-744诱导的细胞迁移和侵袭增强。ARHGAP5的高水平与miR-744的高水平、鼻咽癌的晚期阶段以及淋巴结转移呈正相关。综上所述,这些数据首次揭示miR-744通过直接靶向ARHGAP5启动子发挥其原癌基因功能。这一新发现的miR-744/ARHGAP5途径为鼻咽癌的进展和转移提供了进一步的见解,并指出了鼻咽癌潜在的新治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f01/4537006/68ebfd741018/oncotarget-06-13164-g001.jpg

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