Department of Hematology and Oncology, Hiroshima University, Hiroshima, Japan.
Cancer Sci. 2012 Jan;103(1):34-41. doi: 10.1111/j.1349-7006.2011.02121.x. Epub 2011 Nov 20.
The expression of BMI-1 is correlated with disease progression in cancer patients. We showed that ectopic expression of BMI-1 in B-cell lymphoma cell lines, HT and RL, conferred resistance to etoposide and oxaliplatin, known to enhance sensitivity by targeting the survivin gene, but not to irinotecan, which is not relevant to the downregulation of survivin expression. The expression of survivin was not only augmented in cells transduced with BMI-1, but persisted in the presence of etoposide in cells overexpressing BMI-1. By contrast, the mock-transduced cells succumbed in the medium with anticancer drugs, with an accompanying decrease in BMI-1 and survivin expression. BMI-1 overexpression stabilized survivin post-translationally without an accompanying rise in the mRNA, suggesting survivin as a potential target for BMI-1. Knockdown of either BMI-1 or survivin restored sensitivity to etoposide in the BMI-1-overexpressing lymphoma cells. An analysis of six patients with B-cell lymphoma showed that in the drug-resistant patients, levels of BMI-1 and survivin were maintained even after drug administration. However, downregulation of both BMI-1 and survivin expression was observed in the drug-sensitive patients. Therefore, BMI-1 might facilitate drug resistance in B-cell lymphoma cells through the regulation of survivin. BMI-1 could be an important prognostic marker as well as a future therapeutic target in the treatment of drug-resistant lymphomas.
BMI-1 的表达与癌症患者的疾病进展相关。我们发现，BMI-1 在 B 细胞淋巴瘤细胞系 HT 和 RL 中的异位表达赋予了对依托泊苷和奥沙利铂的耐药性，已知这两种药物通过靶向生存素基因来增强敏感性，但对伊立替康没有作用，伊立替康与生存素表达下调无关。不仅在转导了 BMI-1 的细胞中，而且在过表达 BMI-1 的细胞中存在依托泊苷时，生存素的表达也被增强。相比之下，模拟转导的细胞在含有抗癌药物的培养基中死亡，同时伴随 BMI-1 和生存素表达下降。BMI-1 过表达在没有伴随 mRNA 升高的情况下稳定了生存素的翻译后水平，这表明生存素可能是 BMI-1 的一个潜在靶点。敲低 BMI-1 或生存素均可恢复 BMI-1 过表达淋巴瘤细胞对依托泊苷的敏感性。对 6 例 B 细胞淋巴瘤患者的分析表明，在耐药患者中，即使在给药后，BMI-1 和生存素的水平仍保持不变。然而，在药物敏感的患者中观察到 BMI-1 和生存素表达均下调。因此，BMI-1 可能通过调节生存素促进 B 细胞淋巴瘤细胞的耐药性。BMI-1 可能是治疗耐药性淋巴瘤的一个重要预后标志物和未来治疗靶点。
