Makishi Shoko, Okudaira Taeko, Ishikawa Chie, Sawada Shigeki, Watanabe Toshiki, Hirashima Mitsuomi, Sunakawa Hajime, Mori Naoki
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
Br J Haematol. 2008 Aug;142(4):583-94. doi: 10.1111/j.1365-2141.2008.07229.x. Epub 2008 May 22.
The identification of galectin-9 as a ligand for T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3), expressed on T-helper type-1 (Th1) cells, has established the Tim-3-galectin-9 pathway as a regulator of Th1 immunity. Whereas there is compelling evidence for the effects of galectin-9 on T-cell fate, limited information is available on the impact of galectin-9 on B lymphocytes. We found that protease-resistant galectin-9, hG9NC(null), but not galectin-1 or -8, prevented cell growth of malignant B cells, such as Burkitt lymphoma (BL) and Hodgkin lymphoma (HL). beta-galactoside binding was essential for galectin-9-induced cell growth suppression. hG9NC(null) induced cell cycle arrest by reducing the expression of cyclin D1, D2, B1, Cdk4, Cdc25C and c-Myc, and apoptosis by reducing the expression of XIAP, c-IAP2 and survivin. Most of the genes that encode these proteins are regulated by nuclear factor-kappaB (NF-kappaB), and constitutive activation of NF-kappaBeta is a common characteristic of both types of malignancies. hG9NC(null) inhibited IkappaBalpha phosphorylation, resulting in suppression of NF-kappaB. AP-1 has also been implicated in the control of cell survival. hG9NC(null) inhibited the expression of JunD, resulting in the suppression of AP-1. Our results suggest that hG9NC(null) is a potentially suitable agent for the management of BL and HL.
半乳糖凝集素-9作为表达于1型辅助性T细胞（Th1）上的含T细胞免疫球蛋白和粘蛋白结构域分子-3（Tim-3）的配体被鉴定出来，这确立了Tim-3-半乳糖凝集素-9通路作为Th1免疫的调节因子。尽管有令人信服的证据表明半乳糖凝集素-9对T细胞命运有影响，但关于半乳糖凝集素-9对B淋巴细胞影响的信息有限。我们发现，具有蛋白酶抗性的半乳糖凝集素-9，即hG9NC（无活性），而非半乳糖凝集素-1或-8，可抑制恶性B细胞如伯基特淋巴瘤（BL）和霍奇金淋巴瘤（HL）的细胞生长。β-半乳糖苷结合对于半乳糖凝集素-9诱导的细胞生长抑制至关重要。hG9NC（无活性）通过降低细胞周期蛋白D1、D2、B1、细胞周期蛋白依赖性激酶4（Cdk4）、细胞周期蛋白依赖性激酶25C（Cdc25C）和c-Myc的表达诱导细胞周期停滞，并通过降低X连锁凋亡抑制蛋白（XIAP）、细胞凋亡抑制蛋白2（c-IAP2）和生存素的表达诱导细胞凋亡。大多数编码这些蛋白的基因受核因子-κB（NF-κB）调控，NF-κB的组成性激活是这两种恶性肿瘤的共同特征。hG9NC（无活性）抑制IκBα磷酸化，从而抑制NF-κB。激活蛋白-1（AP-1）也参与细胞存活的调控。hG9NC（无活性）抑制JunD的表达，从而抑制AP-1。我们的结果表明，hG9NC（无活性）可能是治疗BL和HL的合适药物。
