PAUF Induces Migration of Human Pancreatic Cancer Cells Exclusively via the TLR4/MyD88/NF-κB Signaling Pathway

Int J Mol Sci. 2022 Sep 27;23(19):11414. doi: 10.3390/ijms231911414.


PAUF, a tumor-promoting protein secreted by cancer cells, exerts paracrine effects on immune cells through TLR4 receptors expressed on immune cell surfaces. This study aimed to investigate if PAUF elicits autocrine effects on pancreatic cancer (PC) cells through TLR4, a receptor that is overexpressed on PC cells. In this study, TLR4 expression was detected in PC cells only, but not normal pancreatic cells. The migration of TLR4 high-expressing PC cells (i.e., BxPC-3) was reduced by a selective TLR4 inhibitor, in a dose-dependent manner. Using TLR4 overexpressed and knockout PC cell lines, we observed direct PAUF-TLR4 binding on the PC cell surfaces, and that PAUF-induced cancer migration may be mediated exclusively through the TLR4 receptor. Further experiments showed that PAUF signaling was passed down through the TLR4/MyD88 pathway without the involvement of the TLR4/TRIF pathway. TLR4 knockout also downregulated PC membrane PD-L1 expression, which was not influenced by PAUF. To the best of our knowledge, TLR4 is the first receptor identified on cancer cells that mediates PAUF's migration-promoting effect. The results of this study enhanced our understanding of the mechanism of PAUF-induced tumor-promoting effects and suggests that TLR4 expression on cancer cells may be an important biomarker for anti-PAUF treatment.

Keywords: MyD88; NF-κB; PAUF; PD-L1; TLR4; pancreatic cancer; toll-like receptors.

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism
  • Cell Movement / genetics
  • Cell Movement / physiology
  • Humans
  • Intercellular Signaling Peptides and Proteins* / genetics
  • Intercellular Signaling Peptides and Proteins* / metabolism
  • Lectins / metabolism
  • Myeloid Differentiation Factor 88* / genetics
  • Myeloid Differentiation Factor 88* / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • NF-kappa B p50 Subunit* / genetics
  • NF-kappa B p50 Subunit* / metabolism
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / metabolism
  • Signal Transduction
  • Toll-Like Receptor 4* / genetics
  • Toll-Like Receptor 4* / metabolism


  • Adaptor Proteins, Vesicular Transport
  • B7-H1 Antigen
  • CD274 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Lectins
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • ZG16B protein, human