miR-34a, miR-424 and miR-513 inhibit MMSET expression to repress endometrial cancer cell invasion and sphere formation.
miR-34a, miR-424 and miR-513 inhibit MMSET expression to repress endometrial cancer cell invasion and sphere formation.
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DOI：
10.18632/oncotarget.25298
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发表时间：
2018-05-01
期刊：
影响因子：
--
通讯作者：
Watari H
中科院分区：
文献类型：
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作者：
Dong P;Xiong Y;Yue J;Hanley SJB;Watari H
虽然癌基因MMSET（也称为NSD 2或WHSC 1）在恶性肿瘤中具有重要作用，但其对人类子宫内膜癌（EC）转移的影响以及MMSET调控的分子机制在很大程度上是未知的。我们报告，MMSET在EC细胞系和EC组织中显著上调，并且与EC的存活率差显著相关。MMSET过表达可显著促进EC细胞的侵袭和球体形成，而抑制MMSET则可降低EC细胞的侵袭和球体形成。重要的是，Twist 1是MMSET诱导的EC细胞侵袭和球体形成所必需的。此外，我们证明miR-34 a、miR-424和miR-513直接调节MMSET表达，以减弱EC细胞的侵袭和球体形成能力。与正常组织相比，miR-34 a、miR-424和miR-513在EC中下调，并且miR-34 a、miR-424和miR-513的表达减少与EC患者的较差预后临床相关。此外，用BIX-01294特异性抑制MMET导致EC细胞侵袭减少和球体形成受损。这些发现表明MMSET在EC中的促转移作用，并揭示miR-34 a、miR-424和miR-513的抑制有助于EC转移期间MMSET的过表达。
Although the oncogene MMSET (also known as NSD2 or WHSC1) has an essential role in malignancies, its impact on human endometrial cancer (EC) metastasis and the molecular mechanism of MMSET regulation are largely unknown. We report that MMSET was markedly upregulated in EC cell lines and EC tissues, and was significantly associated with poor survival in EC. MMSET overexpression greatly promoted EC cell invasion and sphere formation, whereas inhibition of MMSET reduced EC cell invasion and sphere formation. Importantly, Twist1 was required for MMSET-induced EC cell invasion and sphere formation. Moreover, we demonstrate that miR-34a, miR-424 and miR-513 directly modulate MMSET expression to attenuate the invasion and sphere formation capacity of EC cells. miR-34a, miR-424 and miR-513 were down-regulated in EC compared with normal tissue, and reduced expression of miR-34a, miR-424 and miR-513 was clinically associated with a poorer prognosis in EC patients. Furthermore, specific inhibition of MMET with BIX-01294 led to decreased EC cell invasion and impaired sphere formation. These findings suggest a pro-metastatic role for MMSET in EC and reveal that the repression of miR-34a, miR-424 and miR-513 contributes to the overexpression of MMSET during EC metastasis.