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Pancreatic adenocarcinoma upregulated factor promotes metastasis by regulating TLR/CXCR4 activation

Oncogene volume 30, pages 201–211 (2011)Cite this article

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Abstract

Pancreatic adenocarcinoma upregulated factor (PAUF) is overproduced in certain types of cancer. However, little is known of the tumorigenic function of PAUF. In this study, we report the X-ray crystal structure of PAUF and reveal that PAUF is a mammalian lectin normally found in plant lectins. We also identify PAUF as an endogenous ligand of Toll-like receptor 2 (TLR2) and TLR4 by screening extracellular domain receptor pools. We further confirmed the specificity of the PAUF–TLR2 interaction. PAUF induces extracellular signal-regulated kinase (ERK) phosphorylation and activates the IKK-β-mediated TPL2/MEK/ERK signaling pathway through TLR2. In agreement with the result of TLR2-mediated ERK activation by PAUF, PAUF induces increased expression of the protumorigenic cytokines RANTES and MIF in THP-1 cells. However, PAUF does not fully activate Iκ-B-α signaling pathways in THP-1 cells, and fails to translocate the p65 subunit of the nuclear factor-κB (NF-κB) complex into the nucleus, resulting in no NF-κB activation. Surprisingly, we found that PAUF also associated with the CXC chemokine receptor (CXCR4)–TLR2 complex and inhibited CXCR4-dependent, TLR2-mediated NF-κB activation. Together, these findings suggest that the new cancer-associated ligand, PAUF, may activate TLR-mediated ERK signaling to produce the protumorigenic cytokines, but inhibits TLR-mediated NF-κB signaling, thereby facilitating tumor growth and escape from innate immune surveillance.

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Acknowledgements

This study was supported by grants from the National Creative Research Initiative Center Program, World Class University (WCU) program and the 21st Century Frontier Functional Human Genome Project of the Ministry of Education, Science and Technology in Korea. We thank Sang Yong Hong for technical support with the cloning work. We thank the staff of Beamline 4A at the Pohang Accelerator Laboratory, Korea, for assistance in data collection and Dr Hyun Kyu Song of Korea University for help with MAD data analysis.

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Author notes

  1. H D Park and Y Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Science, National Creative Research Initiative Center for Cell Division and Differentiation, Daejeon, Korea

    H D Park, Y Lee & D-S Lim

  2. Department of Pharmacology, Research and Development Park, LG Life Sciences, Daejeon, Korea

    H D Park & Y K Oh

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

    Y Lee, J G Jung, Y W Park, K-H Kim & S S Koh

  4. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    K Myung

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  1. H D Park
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Correspondence to S S Koh or D-S Lim.

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Park, H., Lee, Y., Oh, Y. et al. Pancreatic adenocarcinoma upregulated factor promotes metastasis by regulating TLR/CXCR4 activation. Oncogene 30, 201–211 (2011). https://doi.org/10.1038/onc.2010.401

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