Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer.
Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer.
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DOI：
10.1158/0008-5472.can-09-1499
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发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Huang TH
中科院分区：
文献类型：
--
作者：
Huang YW;Liu JC;Deatherage DE;Luo J;Mutch DG;Goodfellow PJ;Miller DS;Huang TH
已知基因扩增，突变和易位在癌细胞中致癌基因的上调中起因果作用。在这里，我们报告了microRNA的新作用，其表观遗传失调也可能导致这种致癌激活。SOX4是一种属于sry相关高迁移率群盒家族的癌基因，与未参与的对照组（n=20）相比，在子宫内膜肿瘤（n=74）中发现过表达（P<0.005）。通过计算，该基因被预测为microRNA miR-129-2的靶标。与匹配的子宫内膜相比，31例原发性子宫内膜肿瘤中有27例miR-129-2表达缺失，同时SOX4表达增加（P<0.001）。这种反比关系与miR-129-2 CpG岛的高甲基化有关，这在子宫内膜癌细胞系（n=6）和117例子宫内膜样子宫内膜肿瘤中有68%被观察到。通过药物诱导组蛋白乙酰化和DNA去甲基化在癌细胞中重新激活miR-129-2导致SOX4表达降低。此外，通过细胞转染恢复miR-129-2，导致SOX4表达降低，癌细胞增殖减少。进一步分析发现，miR-129-2高甲基化与微卫星不稳定性和MLH1甲基化状态显著相关（P<0.001），患者总生存期较差（P<0.039）。因此，这些结果暗示SOX4的异常表达在一定程度上是由miR-129-2在子宫内膜癌中的表观遗传抑制引起的。与启动子低甲基化可能上调致癌基因的观点不同，我们提出了一种新的范式，在这种范式中，高甲基化介导的microRNA沉默可以抑制癌细胞中的致癌靶标。
Genetic amplification, mutation, and translocation are known to play a causal role in the up-regulation of an oncogene in cancer cells. Here we report an emerging role of microRNA, the epigenetic deregulation of which may also lead to this oncogenic activation. SOX4, an oncogene belonging to the SRY-related high-mobility-group-box family, was found to be over-expressed (P<0.005) in endometrial tumors (n=74) compared with uninvolved controls (n=20). This gene is computationally predicted to be the target of a microRNA, miR-129-2. When compared to the matched endometria, the expression of miR-129-2 was lost in 27 of 31 primary endometrial tumors that also showed a concomitant gain of SOX4 expression (P<0.001). This inverse relationship is associated with hypermethylation of the miR-129-2 CpG island, which was observed in endometrial cancer cell lines (n=6) and 68% of 117 endometrioid endometrial tumors analyzed. Reactivation of miR-129-2 in cancer cells by pharmacological induction of histone acetylation and DNA demethylation resulted in decreased SOX4 expression. In addition, restoration of miR-129-2 by cell transfection led to decreased SOX4 expression and reduced proliferation of cancer cells. Further analysis found a significant correlation of hypermethylated miR-129-2 with microsatellite instability and MLH1 methylation status (P<0.001), and poor overall survival (P<0.039) in patients. Therefore, these results imply that the aberrant expression of SOX4 is, in part, caused by epigenetic repression of miR-129-2 in endometrial cancer. Unlike the notion that promoter hypomethylation may up-regulate an oncogene, we present a new paradigm in which hypermethylation-mediated silencing of a microRNA de-represses its oncogenic target in cancer cells.