DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/ERK/uPA.
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.
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Xiangyi
X
He
Zhong
Z
Zheng
Jianfang
J
Li
Qiwen
Q
Ben
Jun
J
Liu
Jianian
J
Zhang
Jun
J
Ji
Beiqin
B
Yu
Xuehua
X
Chen
Liping
L
Su
Lin
L
Zhou
Bingya
B
Liu
Yaozong
Y
Yuan
D008841:Actin Cytoskeleton; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D000071617:Protein Deglycase DJ-1; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator / Q000096:biosynthesis / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000378:metabolism*; D019061:src-Family Kinases / Q000096:biosynthesis / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; C051321:SERPINE1 protein, human; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D014568:Urokinase-Type Plasminogen Activator