Abe Anna, Kuwata Takeshi, Yamauchi Chisako, Higuchi Youichi, Ochiai Atsushi
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.
Pathol Int. 2014 Jun;64(6):267-75. doi: 10.1111/pin.12167.
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.
高迁移率族蛋白B1（HMGB1）是炎症介质之一，与肿瘤发生有关。胃腺癌组织中的晚期糖基化终产物受体（RAGE）-HMGB1促进胃癌生长，然而，关于胃癌中HMGB1表达与癌症相关炎症之间的关系尚无报道。成纤维细胞在发生炎症的癌组织中最为丰富。因此，我们研究了癌细胞释放的HMGB1对成纤维细胞的影响。在人胃癌标本中，通过免疫组织化学评估癌细胞中HMGB1的表达和成纤维细胞中核因子-κB（NF-κB）的表达。在更深的浸润处检测到癌细胞中的细胞质HMGB1表达和成纤维细胞中NF-κB的核转位。为了确定癌细胞释放的HMGB1是否诱导成纤维细胞中促炎细胞因子的表达，我们分析了Toll样受体（TLR）信号的激活。重组HMGB1和HSC44PE条件培养基刺激的成纤维细胞显示白细胞介素-1受体相关激酶4（IRAK4）磷酸化、NF-κB核转位以及促炎细胞因子表达增强。用转染了siRNA-HMGB1的HSC44PE条件培养基处理可降低成纤维细胞中促炎细胞因子的表达。我们提出，癌细胞释放的HMGB1通过HMGB1-TLR2/4途径诱导腹膜成纤维细胞中促炎细胞因子的表达。
