Block of proliferation 1 (BOP1) plays an oncogenic role in hepatocellular carcinoma by promoting epithelial-to-mesenchymal transition

Abstract

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 γ-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. Our findings underline an important role for BOP1 in HCC invasiveness and metastasis potentials through inducing EMT and promoting actin cytoskeleton remodeling.