Activation of Toll-like receptor 7 regulates the expression of IFN-λ1, p53, PTEN, VEGF, TIMP-1 and MMP-9 in pancreatic cancer cells.

Abstract

Toll-like receptors (TLRs) are critical in the induction of the immune response in tumor development. TLR7 has previously been demonstrated to be associated with the development of pancreatic cancer, and the release of cytokines and chemokines from other types of cancer cell; however, the specific expression induced by TLR7 agonists in pancreatic cancer cells remains to be elucidated. The present study aimed to investigate the effects of the TLR7 agonist, gardiquimod, on ERK1/2 signaling pathway, and on the expression of genes involved in the pathogenesis of cancer, including phosphatase and tensin homolog deleted on chromosome 10 (PTEN), p53, type Ⅲ interferon (IFN-λ1), vascular endothelial growth factor (VEGF), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). The results demonstrated that activation of TLR7 upregulated the expression levels of certain genes to varying degrees; the expression levels of IFN-λ1 and MMP-9 were increased by ~3 fold, whereas other genes (p53, PTEN, TIMP-1) were upregulated by ~2 fold, and VEGF was marginally upregulated after 10 min. Furthermore, gardiquimod increased the expression levels of phosphorylated-extracellular signal-regulated kinase (ERK)1/2. In addition, PD98059, a specific inhibitor of ERK phosphorylation, inhibited the ability of gardiquimod to activate ERK1/2; consequently weakening the effect of gardiquimod on gene regulation. These findings indicated that the effect of TLR7 agonists, including gardiquimod, on gene expression in BxPC-3 pancreatic cancer cells was partly associated with the mitogen-activated protein kinase-ERK1/2 signaling pathway.

• Authors: Fang Wang, Rui Jin, Bing-Bing Zou, Lei Li, Feng-Wei Cheng, Xin Luo, Xiaoping Geng, Sheng-Quan Zhang
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 13 Issue 2 Pg. 1807-12 (Feb 2016) ISSN: 1791-3004 [Electronic] Greece
• PMID: 26718740 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminoquinolines
• Flavonoids
• IFNL1 protein, human
• Imidazoles
• Interleukins
• TLR7 protein, human
• Tissue Inhibitor of Metalloproteinase-1
• Toll-Like Receptor 7
• Tumor Suppressor Protein p53
• Vascular Endothelial Growth Factor A
• gardiquimod
• Interferons
• Extracellular Signal-Regulated MAP Kinases
• PTEN Phosphohydrolase
• PTEN protein, human
• Matrix Metalloproteinase 9
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Aminoquinolines (pharmacology)
• Cell Line, Tumor
• Enzyme Activation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Flavonoids (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Imidazoles (pharmacology)
• Interferons
• Interleukins (genetics, metabolism)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• PTEN Phosphohydrolase (genetics, metabolism)
• Pancreatic Neoplasms (genetics)
• Phosphorylation (drug effects)
• Tissue Inhibitor of Metalloproteinase-1 (genetics, metabolism)
• Toll-Like Receptor 7 (metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Up-Regulation (drug effects)
• Vascular Endothelial Growth Factor A (genetics, metabolism)