Block of Proliferation 1 (BOP1) Plays an Oncogenic Role in Hepatocellular Carcinoma by Promoting Epithelial-to-Mesenchymal Transition
Block of Proliferation 1 (BOP1) Plays an Oncogenic Role in Hepatocellular Carcinoma by Promoting Epithelial-to-Mesenchymal Transition
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DOI：
10.1002/hep.24372
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发表时间：
2011-07-01
期刊：
影响因子：
13.5
通讯作者：
Wong, Nathalie
中科院分区：
文献类型：
--
作者：
Chung, Kit-Ying;Cheng, Ibis K-C;Wong, Nathalie
区域染色体8 q24的基因组扩增是人类癌症中的常见事件。在肝细胞癌（HCC）中，可在>50%的病例中检测到快速致命的高度侵袭性恶性肿瘤、复发性8 q24增益。在这项研究中，试图解决8 q24区域的阵列比较基因组杂交的方式在HCC中受影响的基因显示了独特的收益的增殖阻滞1（BOP 1）。在原发性肝癌的独立队列中（n = 65）的基因表达评估显示，与邻近的非肿瘤性肝脏相比，肿瘤中的BOP 1频繁上调（84.6%; P < 0.0001）。BOP 1的表达增加与晚期HCC分期（P = 0.004）、微血管浸润（P = 0.006）和患者无病生存期缩短（P = 0.02）之间也存在显著相关性。在同一系列原发性肝癌病例中，对C-MYC（一种位于BOP 1附近的众所周知的癌基因）表达的检测并未提示强的临床病理学相关性。小干扰RNA介导的BOP 1抑制剂对肝癌细胞的功能研究表明，BOP 1能显著抑制肝癌细胞的侵袭（P < 0.005）和迁移（P < 0.05）。BOP 1在永生化肝细胞系L02中过表达，细胞侵袭力和细胞迁移率增加（P < 0.0001）。在基因敲除和异位表达试验中，BOP 1对细胞活力和增殖没有影响。在BOP 1敲低细胞中，上皮-间质转化（EMT）表型明显消退，而上皮标志物（E-钙粘蛋白、细胞角蛋白18和γ-连环蛋白）上调，间质标志物（纤连蛋白和波形蛋白）下调。在L02中，BOP 1的异位表达表明EMT相应增强。此外，BOP 1还能刺激肌动蛋白应力纤维的组装和RhoA的激活。结论：我们的研究结果强调了BOP 1通过诱导EMT和促进肌动蛋白细胞骨架重塑在HCC侵袭和转移潜能中的重要作用。（肝脏学2011;54：307-318）
Genomic amplification of regional chromosome 8q24 is a common event in human cancers. In hepatocellular carcinoma (HCC), a highly aggressive malignancy that is rapidly fatal, recurrent 8q24 gains can be detected in >50% of cases. In this study, attempts to resolve the 8q24 region by way of array comparative genomic hybridization for affected genes in HCC revealed distinctive gains of block of proliferation 1 (BOP1). Gene expression evaluation in an independent cohort of primary HCC (n = 65) revealed frequent BOP1 up-regulation in tumors compared with adjacent nontumoral liver (84.6%; P < 0.0001). Significant associations could also be drawn between increased expressions of BOP1 and advance HCC staging (P = 0.004), microvascular invasion (P = 0.006), and shorter disease-free survival of patients (P = 0.02). Examination of expression of C-MYC, a well-known oncogene located in proximity to BOP1, in the same series of primary HCC cases did not suggest strong clinicopathologic associations. Functional investigations by small interfering RNA mediated suppression of BOP1 in HCC cell lines indicated significant inhibition on cell invasion (P < 0.005) and migration (P < 0.05). Overexpression of BOP1 in the immortalized hepatocyte cell line L02 showed increase cellular invasiveness and cell migratory rate (P < 0.0001). In both gene knockdown and ectopic expression assays, BOP1 did not exert an effect on cell viability and proliferation. Evident regression of the epithelial-mesenchymal transition (EMT) phenotype was readily identified in BOP1 knockdown cells, whereas up-regulation of epithelial markers (E-cadherin, cytokeratin 18, and gamma-catenin) and down-regulation of mesenchymal markers (fibronectin and vimentin) were seen. A corresponding augmentation of EMT was indicated from the ectopic expression of BOP1 in L02. In addition, BOP1 could stimulate actin stress fiber assembly and RhoA activation. Conclusion: Our findings underline an important role for BOP1 in HCC invasiveness and metastasis potentials through inducing EMT and promoting actin cytoskeleton remodeling. (HEPATOLOGY 2011;54:307-318)