Invasion potential of H22 hepatocarcinoma cells is increased by HMGB1-induced tumor NF-κB signaling via initiation of HSP70

Gong,Wei; Wang,Zhi-Yong; Chen,Guo-Xi; Liu,Yu-Qiao; Gu,Xiao-Yan; Liu,Wen-Wei

doi:10.3892/or.2013.2595

Invasion potential of H22 hepatocarcinoma cells is increased by HMGB1-induced tumor NF-κB signaling via initiation of HSP70

Authors:
- Wei Gong
- Zhi-Yong Wang
- Guo-Xi Chen
- Yu-Qiao Liu
- Xiao-Yan Gu
- Wen-Wei Liu
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Affiliations: Department of Oncology, XiangYang Central Hospital, Hubei University of Arts and Science, XiangYang, Hubei 441021, P.R. China, Department of Neurosurgery, XiangYang Central Hospital, Hubei University of Arts and Science, XiangYang, Hubei 441021, P.R. China, Department of Respiratory Medicine, Wuhan Tuberculosis Prevention and Cure Institute, Wuhan, Hubei 430010, P.R. China, Department of Cardiology, XiangYang Central Hospital, Hubei University of Arts and Science, XiangYang, Hubei 441021, P.R. China
Published online on: July 5, 2013 https://doi.org/10.3892/or.2013.2595
Pages: 1249-1256

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Abstract

The functional relationship and cross-regulation between damage-associated molecular patterns and NF‑κB in the tumor microenvironment remains unclear. In the present study, high-mobility group protein B1 (HMGB1) was secreted in response to feed second phase of NF‑κB activation from heat shock protein (HSP) 70 that may result in a higher invasion potential of hepatocarcinoma cells. HSP70 promoted the proliferation of H22 hepatocarcinoma cells through Toll-like receptor (TLR) 2 and TLR4 signaling and induced the early phosphorylation of NF-κB, which reached maximum levels within 30 min. However, HSP70 promoted the upregulation of Beclin-1 expression via Jun N-terminal kinase (JNK) activation in tumor cells and the release of HMGB1 from tumor cells. Inhibition of Beclin-1/c-JNK production prevented the second, but not the first, phase of NF-κB phosphorylation, implicating Beclin-1/c-JNK in the second phase of phosphorylation. HSP70 induced Beclin-1-derived HMGB1 production at 4 h, which occurred before the rise in the second phosphorylation that occurred at 6 h. Exogenous HMGB1 also induced the rapid phosphorylation of NF-κB and upregulated the expression of MMP-9, inhibited the rapid phosphorylation of NF-κB and reduced MMP-9 by receptor for advanced glycation end products (RAGE) inhibitor that prevented HMGB1-induced cell invasion in vitro, which demonstrated that the biological significance of HMGB1/RAGE is key to the second, but not the first, phase of NF-κB phosphorylation in tumor cells. HSP70 triggered a positive feedback loop of NF-κB activation in H22 cells. The second phase of NF-κB phosphorylation mediated by HSP70 is implicated in the increase of tumor cell malignant invasion.

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