Department of Molecular Pathology, Nara Medical University, Kashihara, Japan.
Eur J Cancer. 2010 Mar;46(4):791-9. doi: 10.1016/j.ejca.2009.11.011. Epub 2009 Dec 16.
High mobility group box (HMGB) 1 induces apoptosis of monocyte-lineage cells. We examined the effect of HMGB1 on Kupffer cells (KCs). In 50 Dukes C and 12 liver-metastasised Dukes D colorectal cancers (CRCs), higher HMGB1 concentration in the primary tumours and metastatic foci, and fewer KCs were found in Dukes D cases than in Dukes C cases. The portal blood HMGB1 concentration was higher in Dukes D cases than in Dukes C cases. HMGB1 induced growth inhibition and apoptosis in mouse KCs in a dose-dependent manner, which was associated with the phosphorylation of c-Jun N-terminal kinase (JNK). JNK inhibition and knockdown of HMGB1 receptor abrogated growth inhibition and apoptosis. In a nude mouse liver metastasis model, the caecal administration of HMGB1 decreased the number of KCs and increased the embedment of Colo320 CRC cells in a dose-dependent manner. HMGB1 transfection increased the liver metastasis of Colo320 cells, and the metastasis was inhibited by anti-HMGB1 antibody administration. These results suggest that HMGB1 secreted from primary tumours decreases the number of KCs and attenuates the anti-metastatic defence of the liver in patients with CRCs.
高迁移率族蛋白 B1（HMGB1）诱导单核细胞系细胞凋亡。我们研究了 HMGB1 对枯否细胞（KCs）的影响。在 50 例 Dukes C 期和 12 例肝转移的 Dukes D 期结直肠癌（CRC）中，原发肿瘤和转移灶中 HMGB1 浓度较高，Dukes D 期病例的 KC 较少。Dukes D 期病例的门静脉血 HMGB1 浓度高于 Dukes C 期病例。HMGB1 以剂量依赖性方式诱导小鼠 KC 生长抑制和凋亡，这与 c-Jun N-末端激酶（JNK）的磷酸化有关。JNK 抑制和 HMGB1 受体敲低可消除生长抑制和凋亡。在裸鼠肝转移模型中，盲肠给予 HMGB1 可降低 KC 数量，并呈剂量依赖性增加 Colo320 CRC 细胞的嵌入。HMGB1 转染增加了 Colo320 细胞的肝转移，而抗 HMGB1 抗体的给予则抑制了转移。这些结果表明，原发肿瘤分泌的 HMGB1 可减少 KC 数量，并削弱 CRC 患者肝脏的抗转移防御能力。
