CSN5 promotes the invasion and metastasis of pancreatic cancer by stabilization of FOXM1
CSN5 promotes the invasion and metastasis of pancreatic cancer by stabilization of FOXM1
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DOI：
10.1016/j.yexcr.2018.10.012
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发表时间：
2019-01-15
影响因子：
3.7
通讯作者：
Hu, Junwen
中科院分区：
文献类型：
--
作者：
Mao, Longxi;Le, Shilian;Hu, Junwen
COP 9信号体亚基5（CSN 5）参与了多种人类癌症的进展。MMP 2在癌细胞的转移中起重要作用。然而，在胰腺癌（PC）中的作用和关系仍然未知。在此，我们的数据显示，与相应的癌旁组织相比，CSN 5和MMP 2在PC中均显著上调，其表达与相关的恶性特征呈正相关;此外，CSN 5表达的沉默在体外和体内均显著抑制PC的侵袭和转移，同时伴有MMP 2表达的降低。此外，CSN 5沉默的抗转移作用被MMP 2过表达逆转，而MMP 2的敲低降低了由CSN 5上调驱动的PC转移。进一步的研究表明，CSN 5通过激活PC细胞中的FOXM 1来调节MMP 2的表达。从机制上讲，CSN 5直接结合FOXM 1并降低其泛素化，以增强FOXM 1的蛋白质稳定性。综上所述，结果表明CSN 5可以通过激活FOXM 1/MMP 2轴来促进PC侵袭和转移。
COP9 signalosome subunit 5 (CSN5) has been involved in the progression of diverse human cancers. MMP2 plays an important role in the metastasis of cancer cells. However, the roles and relationship of in pancreatic cancer (PC) is still unknown. Here, our data shown that both CSN5 and MMP2 were significantly upregulated in PC compared with the corresponding adjacent tissues, where a positive correlation in their expression and associated malignant characteristics were found. Further, silencing of CSN5 expression markedly inhibited PC invasion and metastasis in vitro and in vivo, accompanied by decreased MMP2 expression. Moreover, the anti-metastasis role of CSN5 silence was reversed by MMP2 overexpression, whereas knockdown of MMP2 decreased PC metastasis driven by upregulation of CSN5. Further investigation revealed that CSN5 regulated MMP2 expression via activation of FOXM1 in PC cells. Mechanistically, CSN5 directly bound FOXM1 and decreased its ubiquitination to enhance the protein stability of FOXM1. Taken together, the results indicate that CSN5 can contribute to PC invasion and metastasis through activation of FOXM1/MMP2 axis.