Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438, Shanghai, China.
Cell Death Dis. 2018 Jan 19;9(2):59. doi: 10.1038/s41419-017-0090-8.
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is typically diagnosed at advanced stages. Identification and characterisation of genes within amplified and deleted chromosomal loci can provide new insights into the pathogenesis of cancer and lead to new approaches for diagnosis and therapy. In our previous study, we found a recurrent region of copy number amplification at 19p13.2 in hepatocellular carcinoma (HCC). In the present study, we performed integrated copy number analysis and expression profiling at this locus and a putative cancer gene, SMARCA4/BRG1, was uncovered in this region. BRG1 is a part of the large ATP-dependent chromatin remodelling complex SWI/SNF. The function of BRG1 in various cancers is unclear, including its role in HCC tumorigenesis. Here, we found that BRG1 is upregulated in HCC and that its level significantly correlates with cancer progression in HCC patients. Importantly, we also found that nuclear expression of BRG1 predicts early recurrence for HCC patients. Furthermore, we demonstrated that BRG1 promotes HCC cell proliferation in vitro and in vivo. BRG1 was observed not only to facilitate S-phase entry but also to attenuate cell apoptosis. Finally, we discovered that one of the mechanisms by which BRG1 promotes cell proliferation is the upregulation of SMAD6. These findings highlight the important role of BRG1 in the regulation of HCC proliferation and provide valuable information for cancer prognosis and treatment.
肝细胞癌（HCC）是最常见的肝癌形式，通常在晚期诊断。鉴定和描述扩增和缺失染色体基因座内的基因可以提供癌症发病机制的新见解，并为诊断和治疗提供新的方法。在我们之前的研究中，我们在肝细胞癌（HCC）中发现了 19p13.2 染色体区域的重复拷贝数扩增。在本研究中，我们对该基因座和一个假定的癌症基因 SMARCA4/BRG1 进行了综合拷贝数分析和表达谱分析。BRG1 是大型 ATP 依赖性染色质重塑复合物 SWI/SNF 的一部分。BRG1 在各种癌症中的功能尚不清楚，包括其在 HCC 肿瘤发生中的作用。在这里，我们发现 BRG1 在 HCC 中上调，其水平与 HCC 患者的癌症进展显著相关。重要的是，我们还发现 BRG1 预测 HCC 患者的早期复发。此外，我们证明 BRG1 在体外和体内促进 HCC 细胞增殖。观察到 BRG1 不仅促进 S 期进入，而且还减弱细胞凋亡。最后，我们发现 BRG1 促进细胞增殖的机制之一是上调 SMAD6。这些发现强调了 BRG1 在调节 HCC 增殖中的重要作用，并为癌症预后和治疗提供了有价值的信息。
