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

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-beta-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 I kappa-B-alpha signaling pathways in THP-1 cells, and fails to translocate the p65 subunit of the nuclear factor-kappa B (NF-kappa B) complex into the nucleus, resulting in no NF-kappa B activation. Surprisingly, we found that PAUF also associated with the CXC chemokine receptor (CXCR4)-TLR2 complex and inhibited CXCR4-dependent, TLR2-mediated NF-kappa B 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-kappa B signaling, thereby facilitating tumor growth and escape from innate immune surveillance. Oncogene (2011) 30, 201-211; doi:10.1038/onc.2010.401; published online 30 August 2010