Department of General Surgery, the Third Affiliated Hospital of Nanchang University, Nanchang, China.
Department of General Surgery, the Third Affiliated Hospital of Nanchang University, Nanchang, China; Department of Hepatobiliary Surgery, Tumor Hospital of Guanxi Medical University, Nanning, China.
Exp Cell Res. 2019 Jan 15;374(2):274-281. doi: 10.1016/j.yexcr.2018.10.012. Epub 2018 Oct 21.
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.
COP9 信号小体亚基 5（CSN5）参与了多种人类癌症的进展。MMP2 在癌细胞的转移中起着重要作用。然而，CSN5 和 MMP2 在胰腺癌（PC）中的作用和关系尚不清楚。在这里，我们的数据表明，与相应的相邻组织相比，CSN5 和 MMP2 在 PC 中均显著上调，并且发现它们的表达呈正相关，并与恶性特征相关。进一步研究表明，CSN5 表达的沉默显著抑制了体外和体内 PC 的侵袭和转移，同时 MMP2 的表达也降低了。此外，CSN5 沉默的抗转移作用可被 MMP2 的过表达逆转，而 MMP2 的敲低则降低了 CSN5 上调驱动的 PC 转移。进一步的研究表明，CSN5 通过激活 PC 细胞中的 FOXM1 来调节 MMP2 的表达。在机制上，CSN5 直接与 FOXM1 结合并减少其泛素化，从而增强 FOXM1 的蛋白稳定性。总之，这些结果表明，CSN5 可以通过激活 FOXM1/MMP2 轴促进 PC 的侵袭和转移。
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