Dong Peixin, Xiong Ying, Yue Junming, Hanley Sharon J B, Watari Hidemichi
Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
Oncotarget. 2018 May 1;9(33):23253-23263. doi: 10.18632/oncotarget.25298.
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.
尽管致癌基因MMSET（也称为NSD2或WHSC1）在恶性肿瘤中起重要作用，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尚不清楚。我们报告称，MMSET在EC细胞系和EC组织中显著上调，并且与EC患者的不良生存显著相关。MMSET的过表达极大地促进了EC细胞的侵袭和球状体形成，而抑制MMSET则降低了EC细胞的侵袭和球状体形成。重要的是，Twist1是MMSET诱导的EC细胞侵袭和球状体形成所必需的。此外，我们证明miR-34a、miR-424和miR-513直接调节MMSET的表达，以减弱EC细胞的侵袭和球状体形成能力。与正常组织相比，miR-34a、miR-424和miR-513在EC中表达下调，并且miR-34a、miR-424和miR-513的表达降低在临床上与EC患者较差的预后相关。此外，用BIX-01294特异性抑制MMET导致EC细胞侵袭减少和球状体形成受损。这些发现表明MMSET在EC中具有促转移作用，并揭示miR-34a、miR-424和miR-513的抑制在EC转移过程中促成了MMSET的过表达。
