title: High Mobility Group Box1 (HMGB1) released from cancer cells induces the expression of pro-inflammatory cytokines in peritoneal fibroblasts.
abstract: High Mobility Group Box1 protein (HMGB1), one of the mediators of inflammation, is associated with tumorigenesis. The HMGB1-Receptor for advanced glycation end-products (RAGE) in gastric adenocarcinoma tissues promoted gastric cancer growth, however, there are no reports concerning the relationship between the expression of HMGB1 in gastric cancer and cancer-related inflammation. Fibroblasts exist most abundantly on cancer tissue where inflammation occurs. So, we studied the effects of HMGB1 released from cancer cells on the fibroblasts. The expression of HMGB1 in cancer cells and nuclear factor-kappa B (NF-kB) in fibroblasts were evaluated immunohistochemically in human gastric cancer specimens. Cytoplasmic HMGB1 expression in the cancer cells and nuclear translocation of NF-kB in fibroblasts were detected at deeper invasion. To determine whether HMGB1 released from cancer cells induces the expression of pro-inflammatory cytokines in fibroblasts, we analyzed the activation of Toll-like receptor (TLR) signaling. Fibroblasts stimulated by recombinant HMGB1 and the HSC44PE-conditioned medium showed the phosphorylation of Interleukin-1 receptor associated-kinase 4 (IRAK4), nuclear translocation of NF-kB, and enhanced pro-inflammatory cytokine expression. Treatment with HSC44PE-conditioned-medium transfected with siRNA-HMGB1 reduced the expressions of pro-inflammatory cytokines in the fibroblasts. We propose that HMGB1 released from cancer cells induces the expression of pro-inflammatory cytokines in peritoneal fibroblasts through the HMGB1-TLR2/4 pathway.
authors: Laboratory of Cancer Biology, Department of Integrated Bioscience, Graduate School of Frontier Science, The University of Tokyo; Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors: Anna
authors: A
authors: Abe
authors: Takeshi
authors: T
authors: Kuwata
authors: Chisako
authors: C
authors: Yamauchi
authors: Youichi
authors: Y
authors: Higuchi
authors: Atsushi
authors: A
authors: Ochiai
mesh_terms: D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D024243:HMGB1 Protein; D016328:NF-kappa B; D051193:Toll-Like Receptors
keywords: HMGB1; TLR-2; TLR-4; cancer; inflammation; peritoneal fibroblasts