Human Cancer Genomic Research, King Faisal Specialist Hospital and Research, Riyadh 11211 Saudi Arabia.
Haematologica. 2012 Jul;97(7):1092-100. doi: 10.3324/haematol.2011.053421. Epub 2012 Jan 22.
FoxM1 has been shown to play a critical role in the pathogenesis of various epithelial malignancies. However, its role in lymphoid malignancies has not been fully clarified. We, therefore, investigated the role of FoxM1 expression in a large cohort of diffuse large B-cell lymphoma samples and panel of cell lines.
FoxM1 expression was investigated in a large series of diffuse large B-cell lymphoma tissues in a tissue microarray format by immunohistochemistry. Apoptosis was measured by flow cytometry and protein expression was detected by immunoblotting using diffuse large B-cell lymphoma cell lines following treatment with either pharmacological inhibitor of FoxM1 or small interference RNA knockdown strategy. Invasion/migration and soft agar colony assays were also performed following treatment with FoxM1 inhibitor.
FoxM1 expression was detected in 84.6% of diffuse large B-cell lymphoma tumors and found to be significantly associated with proliferative tumor marker Ki67 (P<0.0001), matrix metalloproteinases-2 (P=0.0008), matrix metalloproteinases-9 (P=0.0002), S-phase kinase associated protein-2 (P<0.0001) and inversely associated with p27 expression (P=0.0215). Expression of small interference RNA targeted against FoxM1 or treatment of diffuse large B-cell lymphoma cells with thiostrepton caused its downregulation accompanied by decreased expression of matrix metalloproteinases-2 and matrix metalloproteinases-9. Inhibition of FoxM1 in diffuse large B-cell lymphoma cells also decreased invasive and migratory capability, and induced caspase dependent apoptosis via activation of the mitochondrial apoptotic pathway. Finally, combined thiostrepton and bortezomib at sub-toxic doses led to efficient apoptosis in diffuse large B-cell lymphoma cells.
Altogether, these results suggest that FoxM1 is over-expressed in the majority of diffuse large B-cell lymphoma samples. These data also indicate that targeting FoxM1 signaling can serve as a potential therapeutic modality in the management of diffuse large B-cell lymphoma.
FoxM1 已被证明在各种上皮恶性肿瘤的发病机制中发挥关键作用。然而，其在淋巴恶性肿瘤中的作用尚未完全阐明。因此，我们在大量弥漫性大 B 细胞淋巴瘤样本和细胞系中研究了 FoxM1 表达的作用。
通过免疫组织化学方法在组织微阵列格式中研究了大量弥漫性大 B 细胞淋巴瘤组织中的 FoxM1 表达。通过流式细胞术测量细胞凋亡，并用免疫印迹法检测弥漫性大 B 细胞淋巴瘤细胞系在用 FoxM1 抑制剂或小干扰 RNA 敲低策略处理后的蛋白表达。在用 FoxM1 抑制剂处理后，还进行了侵袭/迁移和软琼脂集落测定。
FoxM1 在 84.6%的弥漫性大 B 细胞淋巴瘤肿瘤中表达，并且与增殖性肿瘤标志物 Ki67 显著相关（P<0.0001）、基质金属蛋白酶-2（P=0.0008）、基质金属蛋白酶-9（P=0.0002）、S 期激酶相关蛋白-2（P<0.0001）和 p27 表达呈负相关（P=0.0215）。针对 FoxM1 的小干扰 RNA 的表达或用噻唑斯汀处理弥漫性大 B 细胞淋巴瘤细胞会导致其下调，同时伴随着基质金属蛋白酶-2 和基质金属蛋白酶-9 的表达降低。在弥漫性大 B 细胞淋巴瘤细胞中抑制 FoxM1 也会降低侵袭和迁移能力，并通过激活线粒体凋亡途径诱导 caspase 依赖性凋亡。最后，在亚毒性剂量下联合使用噻唑斯汀和硼替佐米可有效诱导弥漫性大 B 细胞淋巴瘤细胞凋亡。
总之，这些结果表明 FoxM1 在大多数弥漫性大 B 细胞淋巴瘤样本中过表达。这些数据还表明，靶向 FoxM1 信号可能是管理弥漫性大 B 细胞淋巴瘤的一种潜在治疗方法。
