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PAUF functions in the metastasis of human pancreatic cancer cells and upregulates CXCR4 expression

Oncogene volume 29, pages 56–67 (2010)Cite this article

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.

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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.

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Authors and Affiliations

  1. 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

  2. Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea

    Y Lee, S J Kim, E H Park & S S Koh

  3. School of Science, University of Science & Technology, Daejeon, Korea

    S J Kim & S S Koh

  4. LG Life Sciences, Ltd, R&D Park, Daejeon, Korea

    H D Park & S B Jeon

  5. Department of Pathology, Cancer Research Institute, Chungnam National University College of Medicine, Daejeon, Korea

    S M Huang & J-M Kim

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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

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