Promoter Methylation-mediated Silencing of the MiR-192-5p Promotes Endometrial Cancer Progression by Targeting ALX1.
Promoter Methylation-mediated Silencing of the MiR-192-5p Promotes Endometrial Cancer Progression by Targeting ALX1.
复制标题
启动子甲基化介导的 MiR-192-5p 沉默通过靶向 ALX1 促进子宫内膜癌进展
DOI：
10.7150/ijms.58954
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发表时间：
2021
影响因子：
3.6
通讯作者：
Ren Y
中科院分区：
文献类型：
--
作者：
Ni J;Tian W;Liang S;Wang H;Ren Y
背景：通过启动子甲基化介导的癌症相关microRNA沉默的表观遗传调控在肿瘤发生中起重要作用。MiR-192- 5 p促进各种人类癌症的肿瘤进展，具有相互矛盾的生物学效应。然而，其在子宫内膜癌（EC）中的表达水平及其生物学功能尚未见报道。方法：采用亚硫酸氢盐测序PCR检测组织样本和细胞系中miR-192- 5 p的甲基化状态。还测量了miR-192- 5 p表达。构建了用过表达miR-192- 5 p、其靶基因ALX 1或两者的专门设计的载体转染的EC细胞系。通过体外和体内实验检测这些细胞系的致瘤性。采用双荧光素酶报告基因分析验证miR-192- 5 p的靶点。结果：EC样本中miR-192- 5 p基因启动子区高度甲基化，其表达明显受到抑制。此外，较高水平的启动子甲基化以及较低的miR-192- 5 p表达与根治性切除EC患者的晚期妇产科联盟分期和较短的无病生存期显著相关。功能研究表明，miR-192- 5 p过表达抑制体外肿瘤进展，体内致瘤性和几种与上皮间质转化高度相关的癌蛋白的表达。ALX 1被证实是miR-192- 5 p的直接靶点，并被证明介导miR-192- 5 p的肿瘤抑制功能。结论：miR-192- 5 p是一种通过启动子甲基化而表观遗传学沉默的肿瘤抑制miRNA，可作为EC中潜在的预后生物标志物。
Background: Epigenetic regulation by promoter methylation-mediated silencing of cancer-related microRNAs plays vital roles in tumorigenesis. MiR-192-5p promotes tumor progression in various human cancers with conflicting biological effects. However, its expression levels and biological functions in endometrial carcinoma (EC) have not been reported. Methods: The methylation status of miR-192-5p in tissue samples and cell lines, was examined using bisulfite sequencing PCR. miR-192-5p expression was also measured. EC cell lines transfected with specifically designed vectors overexpressing miR-192-5p, its target gene ALX1 or both, were constructed. Tumorigenicity of these cell lines were examined by in vitro and in vivo experiments. Dual-luciferase reporter assay were employed to verify the target of miR-192-5p. Results: The promoter region of miR-192-5p gene was highly methylated and its expression significantly repressed in EC samples. Moreover, a higher level of promoter methylation as well as a lower expression of miR-192-5p, was significantly associated with advanced Federation of Gynecology and Obstetrics stage and shorter disease-free survival in patients with curatively resected EC. Functional studies demonstrated that miR-192-5p overexpression inhibited in vitro tumor progression, in vivo tumorigenicity and the expression of several oncoproteins that was highly related to epithelial-to-mesenchymal transition. ALX1 was verified as a direct target of miR-192-5p and demonstrated to mediate the tumor-suppressive function of miR-192-5p. Conclusion: miR-192-5p is a tumor suppressor miRNA that is epigenetically silenced by promoter methylation and may serve as a potential prognostic biomarker in EC.
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影响因子：
64.8
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影响因子：
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作者：
Rambow F;Job B;Petit V;Gesbert F;Delmas V;Seberg H;Meurice G;Van Otterloo E;Dessen P;Robert C;Gautheret D;Cornell RA;Sarasin A;Larue L
通讯作者：
Larue L
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45.3
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Esteller, Manel
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Yousef, G. M.
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影响因子：
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作者：
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通讯作者：
Ren, Yulan