Pauf functions in the metastasis of human pancreatic cancer cells and upregulates cxcr4 expression

ABSTRACT 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. Access through your

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ACKNOWLEDGEMENTS This work was supported by grants from the 21st Century Frontier Functional Human Genome Project of the Ministry of Education, Science and Technology, Korea. We thank CK

Jung and MG Kang for statistical analysis, SH Kim for the luciferase reporter plasmids and HJ Hong for critiques of our work. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of

Biological Science, National Research Laboratory, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea Y Lee, H D Park & D-S Lim * Therapeutic Antibody Research

Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea Y Lee, S J Kim, E H Park & S S Koh * School of Science, University of Science & Technology, Daejeon,

Korea S J Kim & S S Koh * LG Life Sciences, Ltd, R&D Park, Daejeon, Korea H D Park & S B Jeon * Department of Pathology, Cancer Research Institute, Chungnam National University

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CORRESPONDING AUTHORS Correspondence to D-S Lim or S S Koh. ADDITIONAL INFORMATION Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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ARTICLE CITE THIS ARTICLE Lee, Y., Kim, S., Park, H. _et al._ PAUF functions in the metastasis of human pancreatic cancer cells and upregulates CXCR4 expression. _Oncogene_ 29, 56–67

(2010). https://doi.org/10.1038/onc.2009.298 Download citation * Received: 25 June 2009 * Revised: 26 July 2009 * Accepted: 23 August 2009 * Published: 28 September 2009 * Issue Date: 07

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link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * PAUF * pancreatic cancer * metastasis *

CXCR4 * signaling