Epigenetically Upregulated MicroRNA-602 Is Involved in a Negative Feedback Loop with FOXK2 in Esophageal Squamous Cell Carcinoma
Epigenetically Upregulated MicroRNA-602 Is Involved in a Negative Feedback Loop with FOXK2 in Esophageal Squamous Cell Carcinoma
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DOI：
10.1016/j.ymthe.2019.07.006
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发表时间：
2019-10-02
影响因子：
12.4
通讯作者：
Sun, Guogui
中科院分区：
文献类型：
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作者：
Liu, Meiyue;Yu, Jiarui;Sun, Guogui
MicroRNA是一种内源性小RNA，控制多个靶基因，在多种肿瘤发生过程中发挥作用。在本研究中，我们的结果显示，食管鳞状细胞癌（ESCC）患者的肿瘤组织和术前血清中的miR-602表达水平高于非肿瘤组织和健康志愿者。 miR-602过表达与淋巴结转移和TNM分期密切相关，总体相关性短，可作为ESCC的独立预后标志物。 miR-602基因的甲基化状态表明，ESCC组织中位于miR-602基因上游的CpG位点比邻近的正常组织更频繁地低甲基化，并且miR-602的甲基化状态与其表达水平成反比。随后，miR-602过表达促进ESCC增殖和转移，并在体外和体内调节细胞周期。从机制上讲，双荧光素酶实验验证了 Fork head box (FOX)K2 (FOXK2) 是 miR-602 的直接靶标。更重要的是，全身递送配制的 miR-602 antagomir 可以减少裸鼠中的肿瘤生长并增加 FOXK2 蛋白表达。这项工作为 ESCC 的分子发病机制提供了新的见解。
MicroRNA is an endogenous, small RNA controlling multiple target genes and playing roles in various tumorigenesis processes. In this study, our results revealed that miR-602 expression levels in tumor tissues and preoperative serum from esophageal squamous cell carcinoma (ESCC) patients were higher than those in non-tumorous tissues and healthy volunteers. miR-602 overexpression was closely related to lymph node metastasis and TNM stages and correlated short overall, and it acted as an independent prognostic marker of ESCC. The methylation status of the miR-602 gene indicated more frequent hypomethylation of the CpG sites located upstream of the miR-602 gene in the ESCC tissues than in the adjacent normal tissues, and the methylation status of miR-602 correlated inversely with its expression levels. Subsequently, miR-602 overexpression promoted ESCC proliferation and metastasis and regulated cell cycles in vitro and in vivo. Mechanistically, a dual-luciferase experiment validated that Fork head box (FOX)K2 (FOXK2) was a direct target of miR-602. More importantly, systemic delivery of formulated miR-602 antagomir could reduce tumor growth and increased FOXK2 protein expression in nude mice. This work provides novel insight into the molecular pathogenesis of ESCC.