Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, P.R., China.
J Cell Biochem. 2013 Sep;114(9):2120-30. doi: 10.1002/jcb.24560.
Bcl-2-associated athanogene-1 (BAG-1) is a multifunctional anti-apoptotic protein which regulates an array of cellular processes, including apoptosis, signaling, proliferation, transcription, and cell motility and has been reported to be over-expressed in a number of human malignancies. To investigate the possible involvement of BAG-1 in tumorigenesis of hepatocellular carcinoma (HCC), we performed Western blot analysis in eight paired samples of HCC and adjacent peritumoral tissues and immunohistochemistry in 65 paraffin sections of HCC, which both showed an enhanced expression of nuclear BAG-1 isoform in HCC tissues. Statistical analysis confirmed that overexpression of nuclear BAG-1 in HCC tissues was significantly associated with histological grading (P < 0.001), poor prognosis (P = 0.004), and was found to be an independent prognostic indicator for HCC (P = 0.023). We also noted that BAG-1 was overexpressed in four HCC cell lines compared with a normal hepatocyte cell line, and BAG-1 overexpression increased resistance of HCC cells to doxorubicin, a common chemotherapeutic agent for HCC. Furthermore, we observed that knock down of BAG-1 with siRNA in HepG2 cells increased the chemosensitivity of cells, a process mediated through inhibition of doxorubicin-triggered NF-κB activation; and knock down of BAG-1 suppressed proliferation and cell cycle transition of HepG2 cells. In consequence, our results for the first time indicated that BAG-1 was dysregulated in HCC and suppression of BAG-1 expression which resulted in inhibiting of NF-κB signaling might be developed into a new strategy in HCC therapy.
Bcl-2 相关抗凋亡基因 1（BAG-1）是一种多功能抗凋亡蛋白，可调节多种细胞过程，包括细胞凋亡、信号转导、增殖、转录、细胞迁移等，并已报道在多种人类恶性肿瘤中过度表达。为了研究 BAG-1 是否参与肝癌（HCC）的肿瘤发生，我们在 8 对 HCC 及相邻肿瘤组织样本中进行了 Western blot 分析，并在 65 例 HCC 石蜡切片中进行了免疫组织化学分析，均显示 HCC 组织中核 BAG-1 同工型表达增强。统计学分析证实，HCC 组织中核 BAG-1 的过表达与组织学分级显著相关（P<0.001），预后不良（P=0.004），并且是 HCC 的独立预后指标（P=0.023）。我们还注意到，与正常肝细胞系相比，BAG-1 在四种 HCC 细胞系中过度表达，BAG-1 过表达增加了 HCC 细胞对阿霉素的耐药性，阿霉素是 HCC 的常用化疗药物。此外，我们观察到 HepG2 细胞中 BAG-1 的 siRNA 敲低增加了细胞的化疗敏感性，这一过程是通过抑制阿霉素触发的 NF-κB 激活介导的；BAG-1 的敲低抑制了 HepG2 细胞的增殖和细胞周期转换。因此，我们的结果首次表明 BAG-1 在 HCC 中失调，抑制 BAG-1 表达从而抑制 NF-κB 信号可能成为 HCC 治疗的新策略。
