Methylation-mediated repression of microRNA-129-2 suppresses cell aggressiveness by inhibiting high mobility group box 1 in human hepatocellular carcinoma.
Methylation-mediated repression of microRNA-129-2 suppresses cell aggressiveness by inhibiting high mobility group box 1 in human hepatocellular carcinoma.
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甲基化介导的 microRNA-129-2 抑制通过抑制人肝细胞癌中的高迁移率族蛋白 1 来抑制细胞侵袭性。
DOI：
10.18632/oncotarget.9377
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发表时间：
2016-06-14
期刊：
影响因子：
--
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Liu Z;Dou C;Yao B;Xu M;Ding L;Wang Y;Jia Y;Li Q;Zhang H;Tu K;Song T;Liu Q
microRNA (miRNA) 的异常表达及其功能障碍已被证明是癌症发生和进展的关键调节因子。据报道，MiR-129-2 在不同的人类恶性肿瘤中发挥肿瘤抑制作用。在这里，我们证明 miR-129-2 在肝细胞癌 (HCC) 组织和细胞系中显着减少。此外，miR-129-2在侵袭性和复发性肿瘤组织中的表达水平显着较低。临床分析表明，miR-129-2的表达与HCC中的静脉浸润、高Edmondson-Steiner分级和晚期肿瘤淋巴结转移（TNM）分期呈负相关。值得注意的是，miR-129-2是指示HCC患者总生存（OS）和无病生存（DFS）的独立预后因素。 miR-129-2 的异位表达在体外和体内抑制细胞迁移和侵袭。此外，我们证实高迁移率族蛋白1（HMGB1）是miR-129-2的直接靶标，并且它消除了miR-129-2在HCC中的功能。机制研究表明，miR-129-2 过表达抑制 AKT Ser473 磷酸化，并降低基质金属蛋白酶2/9 (MMP2/9) 的表达。 p-AKT 的上调消除了 HCC 中 miR-129-2 诱导的细胞迁移和侵袭的减少。而抑制 Akt 磷酸化可显着降低 HMGB1 增强的 HCC 细胞迁移和侵袭。此外，我们发现miR-129-2通过DNA甲基化下调，miR-129-2去甲基化增加HCC细胞中miR-129-2的表达，并对细胞迁移和侵袭产生显着的抑制作用。总之，miR-129-2可以作为HCC患者的预后指标，并至少部分通过抑制HMGB1发挥肿瘤抑制作用。
Aberrant expression of microRNAs (miRNAs) and its dysfunction have been revealed as crucial modulators of cancer initiation and progression. MiR-129-2 has been reported to play a tumor suppressive role in different human malignancies. Here, we demonstrated that miR-129-2 was significantly decreased in hepatocellular carcinoma (HCC) tissues and cell lines. Furthermore, miR-129-2 was expressed at significant lower levels in aggressive and recurrent tumor tissues. Clinical analysis indicated that miR-129-2 expression was inversely correlated with venous infiltration, high Edmondson-Steiner grading and advanced tumor-node-metastasis (TNM) stage in HCC. Notably, miR-129-2 was an independent prognostic factor for indicating overall survival (OS) and disease-free survival (DFS) of HCC patients. Ectopic expression of miR-129-2 inhibited cell migration and invasion in vitro and in vivo. Furthermore, we confirmed that high mobility group box 1 (HMGB1) was a direct target of miR-129-2, and it abrogated the function of miR-129-2 in HCC. Mechanistic investigations showed that miR-129-2 overexpression inhibited AKT phosphorylation at Ser473 and decreased the expression of matrix metalloproteinase2/9 (MMP2/9). Upregulation of p-AKT abolished the decreased cell migration and invasion induced by miR-129-2 in HCC. Whereas inhibition of Akt phosphorylation significantly decreased HMGB1-enhanced HCC cell migration and invasion. Moreover, we found that miR-129-2 was downregulated by DNA methylation, and demethylation of miR-129-2 increased miR-129-2 expression in HCC cells and resulted in significant inhibitory effects on cell migration and invasion. In conclusion, miR-129-2 may serve as a prognostic indicator for HCC patients and exerts tumor suppressive role, at least in part, by inhibiting HMGB1.
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DOI：
10.4137/cgm.s24314
发表时间：
2015
期刊：
Cancer growth and metastasis
影响因子：
--
作者：
Pandey S;Singh S;Anang V;Bhatt AN;Natarajan K;Dwarakanath BS
通讯作者：
Dwarakanath BS
DOI：
10.1146/annurev.pathol.4.110807.092222
发表时间：
2009
期刊：
Annual review of pathology
影响因子：
--
作者：
Lee YS;Dutta A
通讯作者：
Dutta A
影响因子：
11.2
作者：
Huang YW;Liu JC;Deatherage DE;Luo J;Mutch DG;Goodfellow PJ;Miller DS;Huang TH
通讯作者：
Huang TH
影响因子：
3.2
作者：
Bhayani, Neil H.;Jiang, Yixing;Gusani, Niraj J.
通讯作者：
Gusani, Niraj J.
影响因子：
3.4
作者：
Liu, Zhikui;Dou, Changwei;Song, Tao
通讯作者：
Song, Tao