miRNA-34 intrinsically links p53 tumor suppressor and Wnt signaling
miRNA-34 intrinsically links p53 tumor suppressor and Wnt signaling
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DOI：
10.4161/cc.19618
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发表时间：
2012-04-01
期刊：
影响因子：
4.3
通讯作者：
Yook, Jong In
中科院分区：
文献类型：
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作者：
Cha, Yong Hoon;Kim, Nam Hee;Yook, Jong In
尽管在过去的30年里，肿瘤抑制因子p53和经典Wnt级联已经被广泛研究，但由于它们重要的生理作用，这两种信号通路在很大程度上被认为是独立的。最近，发现miR-34家族直接连接p53和Wnt，揭示了肿瘤抑制功能的丧失和致癌信号的激活之间的紧密联系。这些观察结果表明，已知位于p53直接下游的miR-34靶向Wnt和EMT基因UTR中的一组高度保守位点，特别是WNT 1、WNT 3、LRP 6、AXIN 2、β-连环蛋白、LEF 1和Snail，导致TCF/LEF转录活性和EMT程序的抑制。p53功能的丧失增加Wnt活性，并以miR-34/UTR特异性方式在多个水平上促进Snail依赖性EMT程序。TCF/LEF转录特征与临床样本中p53和miR-34的功能密切相关，表明miR-34缺失对人类癌症致癌途径的广泛影响。在这里，我们回顾了最近的研究结果，根据新的数据来阐明p53-miR-34-Wnt网络的生理相关性，其中包括基因组和信号方向。由于wt-p53的丢失或Wnt的过度活化在维持癌症干细胞特性和建立转移程序中至关重要，这些观察结果表明miR介导的准充分性机制连接肿瘤抑制和致癌信号传导途径，支持人类癌症的连续模型。
Though tumor suppressor p53 and the canonical Wnt cascade have been extensively studied for the past 30 years, due to their important physiological roles, the two signaling pathways have been largely considered independent. Recently, the miR-34 family was found to directly link p53 and Wnt, revealing the tight connection between loss of tumor suppressor function and activation of oncogenic signaling. These observations demonstrate that miR-34, known to be directly downstream of p53, targets a set of highly conserved sites in the UTR of Wnt and EMT genes, specifically WNT1, WNT3, LRP6, AXIN2, beta-catenin, LEF1 and Snail, resulting in suppression of TCF/LEF transcriptional activity and the EMT program. The loss of p53 function increases Wnt activities and promotes the Snail-dependent EMT program at multiple levels in a miR-34/UTR-specific manner. The TCF/LEF transcriptional signature was closely associated with functionality of p53 and miR-34 in clinical samples, suggesting the pervasive impact of miR-34 loss on the oncogenic pathway in human cancer. Here, we review recent findings on ceRNA in light of novel data to elucidate the physiological relevance of the p53-miR-34-Wnt network, which encompasses sets of genes and directions of signaling. As loss of wt-p53 or hyperactivation of Wnt is critical in maintaining cancer stem cell properties and in establishing the metastatic program, these observations indicate a mechanism of miR-mediated quasi-sufficiency that connects tumor suppressor and oncogenic signaling pathways, supporting a continuum model of human cancer.