Endaya Berwini, Guan Shou P, Newman Jennifer P, Huynh Hung, Sia Kian C, Chong Siao T, Kok Catherine Y L, Chung Alexander Y F, Liu Bin B, Hui Kam M, Lam Paula Y P
Division of Cellular and Molecular Research, National Cancer Centre, Singapore City, Singapore.
Griffith Health Institute, Griffith University, Southport, Australia.
Oncotarget. 2017 May 5;8(33):54629-54639. doi: 10.18632/oncotarget.17633. eCollection 2017 Aug 15.
The epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein that is regarded as one of the markers for tumor initiating cells (TIC) in human hepatocellular carcinoma (HCC). Much work has been directed towards targeting these TICs as a mean of placing these master regulators of cell proliferation and drug resistance under control. Human bone marrow-derived mesenchymal stem cells are known to exhibit an innate property of tumor tropism. However, the possible relationship between MSC and TIC is not well understood. In this study, we show that MSC migration to HCC can be effectively inhibited by TACE and γ-secretase inhibitors that stop the activation of EpCAM signaling event. Silencing of EpCAM expression through siRNA and antibody approaches also resulted in impaired MSC migration. By contrast, increase levels of EpICD proteins in HCC cells and HCC mouse xenografts resulted in enhanced MSC migration. Taken together, these findings show that MSC is drawn to the more oncogenic population of HCC, and could potentially serve as a cell-based carrier of therapeutic genes to target EpICD-enriched hepatic tumor cells.
上皮细胞粘附分子（EpCAM）是一种I型跨膜糖蛋白，被视为人类肝细胞癌（HCC）中肿瘤起始细胞（TIC）的标志物之一。许多研究致力于靶向这些TIC，以此作为控制这些细胞增殖和耐药性的主要调节因子的一种手段。已知人骨髓间充质干细胞具有肿瘤趋向性的固有特性。然而，间充质干细胞（MSC）与肿瘤起始细胞（TIC）之间的可能关系尚未完全清楚。在本研究中，我们发现，通过抑制肿瘤坏死因子α转换酶（TACE）和γ-分泌酶可有效抑制MSC向肝癌细胞的迁移，这两种酶可阻断EpCAM信号事件的激活。通过小干扰RNA（siRNA）和抗体方法沉默EpCAM表达也会导致MSC迁移受损。相反，肝癌细胞和肝癌小鼠异种移植模型中EpICD蛋白水平的增加会导致MSC迁移增强。综上所述，这些发现表明，间充质干细胞被吸引到肝癌中更具致癌性的细胞群体中，并有可能作为基于细胞的治疗基因载体，靶向富含EpICD的肝肿瘤细胞。
