Phosphoglycerate kinase 1 a promoting enzyme for peritoneal dissemination in gastric cancer.
Peritoneal carcinomatosis is a frequent finding in gastric cancer associated with a poor prognosis. The features that enable gastric tumors to disseminate are poorly understood until now. Previously, we showed elevated mRNA levels of phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate-generating enzyme in the glycolytic pathway, the chemokine receptor 4 (CXCR4), the corresponding chemokine ligand 12 (CXCL12) and beta-catenin in specimens from gastric cancer patients with peritoneal carcinomatosis. In this study, the influence of PGK1 on CXCR4 and beta-catenin was assessed as well as the invasiveness of PGK1 overexpressing cancer cells. In this current study, we found that PGK1 regulates the expression of CXCR4 and beta-catenin at the mRNA and protein levels. On the other hand, CXCR4 regulates the expression of PGK1. Plasmid-mediated overexpression of PGK1 dramatically increased the invasiveness of gastric cancer cells. Interestingly, inhibition of CXCR4 in cells overexpressing PGK1 produced only a moderate reduction of invasiveness suggesting that, PGK1 itself has a critical role in tumor invasiveness. Immunohistochemistry in specimens from diffuse gastric cancer patients also revealed an overexpression of PGK1 in patients with development of peritoneal carcinomatosis. Therefore, PGK1 may be a crucial enzyme in peritoneal dissemination. Together these findings suggest that the enhanced expression of PGK1 and its signaling targets CXCR4 and beta-catenin in gastric cancer cells promote peritoneal carcinomatosis. Thus, PGK1 may serve as prognostic marker and/or be a potential therapeutic target to prevent dissemination of gastric carcinoma cells into the peritoneum.
Zieker
Derek
D
Department of General Visceral, Transplant Surgery Comprehensive Cancer Center, University of Tuebingen, D-72076 Tuebingen, Germany. derek.zieker@med.uni-tuebingen.de
Königsrainer
Ingmar
I
Tritschler
Isabel
I
Löffler
Markus
M
Beckert
Stefan
S
Traub
Frank
F
Nieselt
Kay
K
Bühler
Sarah
S
Weller
Michael
M
Gaedcke
Jochen
J
Taichman
Russell S
RS
Northoff
Hinnak
H
Brücher
Björn L D M
BL
Königsrainer
Alfred
A
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008954:Models, Biological; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D010735:Phosphoglycerate Kinase / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C495270:CTNNB1 protein, human; C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; D051176:beta Catenin; D010735:Phosphoglycerate Kinase
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