Uddin S, Hussain A, Ahmed M, Belgaumi A, Al-Dayel F, Ajarim D, Bavi P, Al-Kuraya K S
Department of Human Cancer Genomic Research, Research Center, King Fahad National Center for Children's Cancer & Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
J Pathol. 2008 Dec;216(4):483-94. doi: 10.1002/path.2433.
S-phase kinase protein 2 (SKP2), an F-box protein, targets cell-cycle regulators including cycle-dependent kinase inhibitor p27KiP1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancer cells and has been implicated in oncogenesis; however, its role in diffuse large B-cell lymphoma (DLBCL) has not been elucidated. Therefore, we investigated the role of SKP2 and its ubiquitin-proteasome pathway in a large series (301) of DLBCL patient samples and a panel of DLBCL cell lines. Using immunohistochemistry, SKP2 was detected in 41.6% of DLBCL tumours and was inversely associated with p27Kip1 protein level. The DLBCL subset with high SKP2 and low p27Kip1 showed a strong correlation with the proliferating index marker Ki-67 (p < 0.0001) and also with the germinal centre phenotype (p = 0.0147). Treatment of DLBCL cell lines with bortezomib or expression of SKP2-specific siRNA causes down-regulation of SKP2 and accumulation of p27Kip1, leading to suppression of growth by inducing apoptosis. Furthermore, treatment of DLBCL cells with bortezomib causes apoptosis via involving the mitochondrial pathway and activation of caspases. Finally, treatment of DLBCL cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Altogether, these results suggest that SKP2 and the ubiquitin-proteasome pathway may be a potential target for therapeutic intervention in DLBCL.
S期激酶相关蛋白2（SKP2）是一种F-box蛋白，它通过泛素介导的降解作用靶向细胞周期调节因子，包括细胞周期蛋白依赖性激酶抑制剂p27KiP1。SKP2在多种癌细胞中经常过度表达，并与肿瘤发生有关；然而，其在弥漫性大B细胞淋巴瘤（DLBCL）中的作用尚未阐明。因此，我们在一大系列（301例）DLBCL患者样本和一组DLBCL细胞系中研究了SKP2及其泛素-蛋白酶体途径的作用。通过免疫组织化学检测，发现41.6%的DLBCL肿瘤中存在SKP2，且其与p27Kip1蛋白水平呈负相关。SKP2高表达且p27Kip1低表达的DLBCL亚组与增殖指数标志物Ki-67（p < 0.0001）以及生发中心表型（p = 0.0147）密切相关。用硼替佐米处理DLBCL细胞系或表达SKP2特异性小干扰RNA会导致SKP2下调和p27Kip1积累，通过诱导凋亡抑制细胞生长。此外，用硼替佐米处理DLBCL细胞会通过线粒体途径和半胱天冬酶激活导致凋亡。最后，用硼替佐米处理DLBCL细胞会下调XIAP、cIAP1和survivin的表达。总之，这些结果表明SKP2和泛素-蛋白酶体途径可能是DLBCL治疗干预的潜在靶点。
