DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/ERK/uPA
DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/ERK/uPA
复制标题
DJ-1通过激活SRC/ERK/uPA促进胰腺癌细胞侵袭和转移
DOI：
10.1093/carcin/bgs002
复制
发表时间：
2012-03-01
期刊：
影响因子：
4.7
通讯作者：
Yuan, Yaozong
中科院分区：
文献类型：
--
作者：
He, Xiangyi;Zheng, Zhong;Yuan, Yaozong
A major hallmark of pancreatic ductal adenocarcinoma (PDAC) is extensive local tumor invasion and early systemic dissemination. DJ-1 has been shown to prevent cell death via the Akt pathway, thereby playing an important role in cancer progression and Parkinson's disease development. Here, we investigated the role of DJ-1 in tumor invasion and metastasis of pancreatic cancer and showed that DJ-1 is upregulated in 68.5% of pancreatic cancer specimens, correlated with tumor stage and predictive of short overall survival. Knockdown of DJ-1 expression in two PDAC cell lines reduced cell migration and invasion potential in vitro and inhibited metastasis in vivo. Knockdown of DJ-1 led to cytoskeleton disruption and diminished urokinase plasminogen activator (uPA) activity and expression, without affecting plasminogen activator inhibitor-1 and uPA receptor (uPAR) expression. All these effects were reversed by restoration of DJ-1 expression. In determining the pathway through which DJ-1 regulated cell migration and invasion, DJ-1 was found not to regulate Akt phosphorylation. Rather, it promoted extracellular signal-regulated kinase (ERK) and SRC phosphorylation. Inhibition of the ERK pathway in PDAC mimicked the effects of DJ-1 on cell migration, invasion, actin cytoskeleton and uPA/uPAR system and abolished the effects on promoting PDAC cell invasion and migration. These data represent the first identification of an important function of DJ-1, which is to regulate the invasion and metastasis properties of PDAC through the ERK/uPA cascade.
