Regulation of migration and invasion by Toll-like receptor-9 signaling network in prostate cancer.

Yun Luo,Jie-Ying Wu,Qi-Wei Jiang,Xiao-Long Mei,Wen-Ji Zhang,Jian-Ge Qiu,Zhi Shi,Jin-Ming Di

doi:10.18632/oncotarget.4197

Yun Luo, Jie-Ying Wu + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.4197

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Journal: Oncotarget	Publication Date: Jun 5, 2015
Citations: 64	License type: cc-by

Affiliation: Sun Yat-sen University, Jinan University

Abstract

Toll-like receptors (TLRs) play an important role in tumorigenesis and progress of prostate cancer. However, the function and mechanism of Toll-like receptor-9 (TLR9) in prostate cancer is not totally understood. Here, we found that high expression of TLR9 was associated with a higher probability of lymph node metastasis and poor prognosis. Further in vitro functional study verified that silence of TLR9 inhibited migration and invasion of PC-3 cells, indicating expression of TLR9 involving in the migration and invasion of cancer cells. The data of microarray exhibited silence of TLR9 induced 205 genes with larger than 2-fold changes in expression levels, including 164 genes down-regulated and 41 genes up-regulated. Functional Gene Ontology (GO) processes annotation demonstrated that the top three scores of molecular and cellular functions were regulation of programmed cell death, regulation of locomotion and response to calcium ion. TLR9 signaling network analysis of the migration and invasion related genes identified several genes, like matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9), chemokine receptor 4 (CXCR4) and interleukin 8 (IL8), formed the core interaction network based on their known biological relationships. A few genes, such as odontogenic ameloblast-associated protein (ODAM), claudin 2 (CLDN2), gap junction protein beta 1 (GJB1) and Rho-associated coiled-coil containing protein kinase 1 pseudogene 1 (ROCK1P1), so far have not been found to interact with the other genes. This study provided the foundation to discover the new molecular mechanism in signaling networks of invasion and metastasis in prostate cancer.

Highlights

Prostate cancer is one of the most common solid organ malignancy affecting men in world
To further determine whether Toll-like receptor-9 (TLR9) expression is associated with prognosis of patients with prostate cancer, progression-free survival rates were compared in patients with high and low TLR9 expression
We found that positive lymph node metastasis (HR:10.54, 95% CI:2.94–37.80, P < 0.001) and preoperative prostate-specific antigen (PSA) (HR:1.27, 95% CI:1.11–1.46, P = 0.001) were independent factors of poor prognosis in prostate cancer, while high TLR9 expression were not an independent factor for predicting prognosis

Summary

Introduction

Prostate cancer is one of the most common solid organ malignancy affecting men in world. Several studies, including meta-analyses, suggest inflammation play an important role on the pathogenesis of prostate cancer [1,2,3]. Previous studies showed that treatment of TLR9-expressing prostate cancer cells with synthetic TLR9-ligands, which mimic the structure of bacterial DNA, stimulates the invasion by increasing the matrix metalloproteinase activity in vitro [15, 16]. These findings suggest that TLR9 could play a role in the tumorigenesis and progress of prostate cancer. The mechanism of cellular DNA receptor TLR9 promoting invasion and metastasis in prostate cancer is still unclear

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