Transcriptional control of PAX4-regulated miR-144/451 modulates metastasis by suppressing ADAMs expression
Transcriptional control of PAX4-regulated miR-144/451 modulates metastasis by suppressing ADAMs expression
复制标题
PAX4 调节的 miR-144/451 的转录控制通过抑制 ADAM 表达来调节转移
DOI：
10.1038/onc.2014.259
复制
发表时间：
2015-06-01
期刊：
影响因子：
8
通讯作者：
Chen, W.
中科院分区：
文献类型：
--
作者：
Zhang, J.;Qin, X.;Chen, W.
配对盒型基因4 （Paired box gene 4, PAX4）是位于染色体7q32上的转录调节因子，在多种人类癌症中表达失调，提示PAX4可能作为驱动基因在多种肿瘤中发挥重要作用。在这里，我们发现PAX4通过降低miR-144和miR-451 （miR-144/451）的表达水平来促进人类上皮癌的迁移和侵袭。因此，miR-144/451抑制迁移和侵袭表型，即使在表达pax4的细胞中也是如此。在机制上，miR-144/451通过靶向A崩解素和金属蛋白酶（ADAM）蛋白家族成员ADAMTS5和ADAM10来抑制癌症转移。它们的失调与肿瘤侵袭性和转移增加有关，然后在某些上皮性癌症中降低患者预后。这一发现表明PAX4-miR-144/451-ADAMs轴调节人类上皮癌转移，从而开辟了这些癌症类型的治疗可能性和预测预后。
Paired box gene 4 (PAX4) is a transcriptional modulator located on chromosome 7q32, and its expression is dysregulated in a variety of human cancers, suggesting that PAX4 may be important in multiple tumors as a driver gene. Here, we show that PAX4 promoted migration and invasion in human epithelial cancers by decreasing miR-144 and miR-451 (miR-144/451) expression levels. Accordingly, miR-144/451 suppressed the migratory and invasive phenotypes, even in PAX4-expressing cells. Mechanistically, miR-144/451 inhibits cancer metastasis by targeting the A disintegrin and metalloproteinase (ADAM) protein family members ADAMTS5 and ADAM10. Their dysregulation is associated with increased tumor invasiveness and metastasis, then reduced patient prognosis in certain epithelial cancers. This discovery suggests that a PAX4–miR-144/451–ADAMs axis regulates human epithelial cancer metastasis, thus opening up therapeutic possibilities and predicting prognosis for those cancer types.