Macrophage migration inhibitory factor enhances autophagy by regulating ROCK1 activity and contributes to the escape of dendritic cell surveillance in glioblastoma
Macrophage migration inhibitory factor enhances autophagy by regulating ROCK1 activity and contributes to the escape of dendritic cell surveillance in glioblastoma
复制标题
巨噬细胞迁移抑制因子通过调节ROCK1活性增强自噬并有助于逃避胶质母细胞瘤中树突状细胞的监视
DOI：
10.3892/ijo.2016.3704
复制
发表时间：
2016-11-01
影响因子：
5.2
通讯作者：
Li, Gang
中科院分区：
文献类型：
--
作者：
Xu, Shugang;Guo, Xing;Li, Gang
巨噬细胞移动抑制因子（MIF）在胶质母细胞瘤中高度表达，促进恶性进展并抑制免疫监视。然而，其在人类胶质母细胞瘤中的生物学作用的机制以及MIF逃避树突状细胞（DC）监视的能力仍然知之甚少。在本研究中，我们发现，重组人MIF（rhMIF）激活RhoA-ROCK 1通路，同时上调F-肌动蛋白纤维的形成。此外，我们发现rhMIF增加了胶质母细胞瘤细胞的自噬，而内源性MIF的敲低抑制了自噬。在胶质瘤标本中，MIF表达与LC 3B水平显著相关。此外，我们证实了Rho相关的卷曲螺旋激酶（ROCK）1的活性在MIF诱导的自噬中起着至关重要的作用。ROCK 1抑制剂Y26736阻断了MIF介导的多形性胶质母细胞瘤（GBM）细胞迁移和集落形成的增加。此外，外源性rhMIF抑制未成熟DC（iDC）和成熟DC（mDC）的迁移。在iDCs成熟过程中加入rhMIF会损害共刺激标志物的表达。综上所述，我们的研究结果确定ROCK 1作为一个关键的调解人的MIF诱导的自噬和免疫抑制作用的MIF对DC监督胶质母细胞瘤。
Macrophage migration inhibitory factor (MIF) is highly expressed in glioblastoma, promoting malignant progression and suppresses immune surveillance. However, the mechanism underlying its biological roles in human glioblastoma and the capability of MIF to escape dendritic cell (DC) surveillance remain poorly understood. In the present study, we folind that recombinant human MIF (rhMIF) activated the RhoA-ROCK1 pathway and simultaneously upregulated F-actin fibre formation. Additionally, we showed that rhMIF increased autophagy in glioblastoma cells, and knockdown of endogenic MIF suppressed autophagy. In glioma specimens, MIF expression was significantly correlated with LC3B levels. Moreover, we confirmed that the activity of Rho-associated coiled-coil containing kinase (ROCK)1 played a crucial role in MIF-induced autophagy. Y26736, a ROCK1 inhibitor, blocked the MIF-mediated increase in migration and colony formation in glioblastoma multiforme (GBM) cells. Furthermore, exogenous rhMIF suppressed the migration of both immature DCs (iDCs) and mature DCs (mDCs). Addition of rhMIF during the maturation process of iDCs impaired the expression of co-stimulatory markers. Taken together, our results identified ROCK1 as a critical mediator of MIF-induced autophagy and the immunosuppressive effect of MIF on DC surveillance in glioblastoma.