Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actin Cytoskeleton
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Carcinoma, Pancreatic Ductal / genetics
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Carcinoma, Pancreatic Ductal / metabolism*
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Carcinoma, Pancreatic Ductal / pathology*
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Cell Line, Tumor
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Cell Movement
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Extracellular Signal-Regulated MAP Kinases / biosynthesis
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Neoplasm Invasiveness
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Neoplasm Metastasis
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Neoplasm Staging
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Oncogene Proteins / biosynthesis
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism*
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Pancreatic Neoplasms / pathology*
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Phosphorylation
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Plasminogen Activator Inhibitor 1 / metabolism
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Protein Deglycase DJ-1
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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RNA, Small Interfering
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Receptors, Urokinase Plasminogen Activator / biosynthesis
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Receptors, Urokinase Plasminogen Activator / metabolism
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Urokinase-Type Plasminogen Activator / biosynthesis
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Urokinase-Type Plasminogen Activator / metabolism*
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src-Family Kinases / biosynthesis
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src-Family Kinases / metabolism*
Substances
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Intracellular Signaling Peptides and Proteins
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Oncogene Proteins
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Plasminogen Activator Inhibitor 1
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RNA, Small Interfering
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Receptors, Urokinase Plasminogen Activator
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SERPINE1 protein, human
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src-Family Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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PARK7 protein, human
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Protein Deglycase DJ-1
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Urokinase-Type Plasminogen Activator