Soluble B7-H3 promotes the invasion and metastasis of pancreatic carcinoma cells through the TLR4/NF-κB pathway

Chao Xie,Qijun Chen,Danqing Liu,Heshui Wu,Bo Wang,Chong Yang

doi:10.1038/srep27528

Abstract

Many studies have demonstrated a relationship between soluble B7-H3 (sB7-H3) and the poor prognosis of patients with malignant tumors, and increasing evidence has shown a connection between sB7-H3 and NF-κB in tumor progression. In the present study, we demonstrate for the first time that sB7-H3 promotes the invasion and metastasis of pancreatic carcinoma cells through the TLR4/NF-κB pathway. In this study, we observed that sB7-H3 was highly expressed in mB7-H3-positive pancreatic carcinoma (PCa) cells. Exogenous sB7-H3 significantly increased NF-κB activity and promoted the migration and invasion of PCa cells. Further studies proved that sB7-H3 first up-regulated TLR4 expression, then activated NF-κB signaling and finally promoted IL-8 and VEGF expression. In contrast, the silencing of TLR4 using a stable short hairpin RNA significantly decreased the sB7-H3-induced activity of NF-κB and the expression of IL-8 and VEGF in PCa cells. In vivo animal experiments further demonstrated that TLR4-knock-down tumor cells displayed a decreased ability to metastasize compared with the control tumor cells after being induced by sB7-H3. Collectively, these results demonstrate that sB7-H3 promotes invasion and metastasis through the TLR4/NF-κB pathway in pancreatic carcinoma cells.

Highlights

NF-κB is a crucial transcription factor that plays a key role in innate and adaptive immunity
We demonstrated that sB7-H3 could enhance the invasive and migratory potential of Pancreatic carcinoma (PCa) cells through the NF-κBpathway
We demonstrated that NF-κBactivity was up-regulated by sB7-H3 in PCa cells and that increased NF-κBactivity may account for the positive correlation between B7-H3-positive tumors and malignant tumorigenesis[21]

Summary

Introduction

NF-κB is a crucial transcription factor that plays a key role in innate and adaptive immunity. Recent research has documented that the constitutive activation of NF-κB is associated with tumorigenesis, invasion and metastasis in human carcinomas[14,15]. A pro-tumorigenic relationship between NF-κB and stat[316] has been demonstrated, in which stat[3] induces constitutive NF-κBactivity in tumors to promote chemoresistance and tumorigenesis. NF-κBsignaling increases the expression of IL-8, VEGF and MMPs in the tumor microenvironment[17,18]. Whether a correlation exists between B7-H3 and NF-κB that facilitates cancer progression requires further investigation. We provide evidence that sB7-H3 increases the activity of NF-κB in a TLR4-dependent manner, which promotes PCa cell invasion and metastasis in vitro and in vivo

Methods

Results

Conclusion