Hung Chin-Sheng, Huang Chien-Yu, Lee Chia-Hwa, Chen Wei-Yu, Huang Ming-Te, Wei Po-Li, Chang Yu-Jia
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
Oncotarget. 2017 Jul 5;8(33):54978-54992. doi: 10.18632/oncotarget.18989. eCollection 2017 Aug 15.
Heat shock protein 27 (Hsp27) is a key chaperone that interacts with over 200 client proteins. The expression of Hsp27 might be correlated with poor outcome in many types of cancer. Previous study indicated that Hsp27 might be an important biomarker in hepatocellular carcinoma (HCC). However, the detailed mechanism is less well understood. The shRNA-mediated silencing of Hsp27 decreased the proliferation, migration and invasion of HCC cells. In a xenograft model, the silencing of Hsp27 reduced tumor progression. We revealed that the silencing of Hsp27 led to a reduction in insulin-like growth factor binding protein 2 (IGFBP2), which might mediate proliferation and metastasis through vimentin, snail and beta-catenin. The overexpression of IGFBP2 reversed the reductions in cell growth, migration and invasion. The tissue array results showed that HCC patients with high Hsp27 expression exhibited poor prognosis and increased metastasis. The Hsp27 expression was highly correlated with IGFPB2 in CRC specimen. ChIP and luciferase assays showed that Hsp27 does not directly bind the IGFBP2 promoter region to regulate the transcription of IGFBP2. In conclusion, our study demonstrated that Hsp27 is a key mediator of HCC progression and metastasis and that Hsp27 might regulate proliferation and metastasis through IGFBP2. This pathway might provide a new direction for the development of a novel therapeutic strategy for HCC.
热休克蛋白27（Hsp27）是一种关键的伴侣蛋白，可与200多种客户蛋白相互作用。Hsp27的表达可能与多种癌症的不良预后相关。先前的研究表明，Hsp27可能是肝细胞癌（HCC）的重要生物标志物。然而，其详细机制尚不清楚。shRNA介导的Hsp27沉默降低了肝癌细胞的增殖、迁移和侵袭能力。在异种移植模型中，Hsp27的沉默减缓了肿瘤进展。我们发现，Hsp27的沉默导致胰岛素样生长因子结合蛋白2（IGFBP2）减少，而IGFBP2可能通过波形蛋白、蜗牛蛋白和β-连环蛋白介导增殖和转移。IGFBP2的过表达逆转了细胞生长、迁移和侵袭能力的降低。组织芯片结果显示，Hsp27高表达的肝癌患者预后较差且转移增加。在结直肠癌标本中，Hsp27表达与IGFPB2高度相关。染色质免疫沉淀和荧光素酶检测表明，Hsp27不直接结合IGFBP2启动子区域来调节IGFBP2的转录。总之，我们的研究表明，Hsp27是肝癌进展和转移的关键介质，并且Hsp27可能通过IGFBP2调节增殖和转移。该途径可能为肝癌新治疗策略的开发提供新方向。
