PAUF functions in the metastasis of human pancreatic cancer cells and upregulates CXCR4 expression.
Pancreatic cancer is characterized by early metastatic spread, but the process of tumor cell dissemination is largely unknown. In this study we show that the soluble protein pancreatic adenocarcinoma upregulated factor (PAUF) has an important role in the metastasis and progression of the disease. Variations in the level of PAUF, either by overexpression or knockdown, resulted in altered migration, invasion and proliferation capacity of pancreatic cancer cells. Moreover, depletion of PAUF in metastatic cells dramatically abrogated the spread of the cells to distant organs in an orthotopic xenograft mouse model. PAUF elicited the activation of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and AKT intracellular signaling cascades and consequently their downstream transcription factors in an autocrine manner. Genome-wide expression analysis revealed that C-X-C chemokine receptor type 4 (CXCR4) expression was induced by PAUF overexpression but was repressed by PAUF knockdown. The PAUF-mediated increase in cancer cell motility was attenuated by the CXCR4 inhibitor, AMD3100, or by anti-CXCR4 antibody. Furthermore, immunohistochemical analysis of pancreatic tumor tissues clearly showed a significant positive correlation between PAUF and CXCR4 expression. Collectively, these findings indicate that PAUF enhances the metastatic potential of pancreatic cancer cells, at least in part, by upregulating CXCR4 expression.
National Research Laboratory, Department of Biological Science, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
Y
Y
Lee
S J
SJ
Kim
H D
HD
Park
E H
EH
Park
S M
SM
Huang
S B
SB
Jeon
J-M
JM
Kim
D-S
DS
Lim
S S
SS
Koh
D000818:Animals; D001596:Benzylamines; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000080027:Cyclams; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins; D019718:Receptors, CXCR4; C517340:ZG16B protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; C088327:plerixafor