DJ-1 Promotes Invasion and Metastasis of Pancreatic Cancer Cells by Activating SRC/ERK/uPA
Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel l'expression du gène DJ-1, impliqué dans la régulation de la mort cellulaire, favorise les processus invasif et métastatique d'un carcinome canalaire du pancréas
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 up-regulated 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 uPA activity and expression, without affecting PAI-1 and uPAR expression. All of 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 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.
http://carcin.oxfordjournals.org/content/early/2012/01/04/carcin.bgs002.abstract