Department of Clinical Laboratory, the Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100039, China.
Beijing Institute of Biotechnology, Beijing 100850, China.
Biochim Biophys Acta Mol Cell Res. 2019 Apr;1866(4):588-597. doi: 10.1016/j.bbamcr.2019.01.001. Epub 2019 Jan 5.
Increased GP73 expression in hepatocytes from patients with acute hepatitis, through disease progression to cirrhosis and chronic liver disease suggests that progressive tissue remodeling and fibrogenesis are driving forces for GP73 upregulation. Nevertheless, details about regulation of GP73 expression and its biological functions remain elusive and await further characterization. In this study, we demonstrate that GP73 is a direct target of TGF-β1 transcriptional regulation. Its induced expression inhibits TGF-β-Smad mediated growth suppression. On the other hand, elevated GP73 results in upregulation of ERK/Akt signaling induced by TGF-β1. Mechanistically, upregulation of lipid raft and caveolae-1 induced by GP73 overexpression mediates its regulatory effect on TGF-β1 signaling. Notably, lipid raft expression is elevated in HCC tumors and tissues with higher GP73 expression yield more intensive Flotillin staining. Our results establish the linkage between GP73 and TGF-β signaling, indicating that GP73 may promote HCC tumorigenesis by selectively regulating TGF-β signaling through lipid raft modulation.
在急性肝炎、进展为肝硬化和慢性肝病的患者的肝细胞中，GP73 的表达增加，这表明进行性组织重塑和纤维化是 GP73 上调的驱动力。然而，关于 GP73 表达的调节及其生物学功能的细节仍不清楚，有待进一步表征。在这项研究中，我们证明 GP73 是 TGF-β1 转录调节的直接靶标。其诱导表达抑制 TGF-β-Smad 介导的生长抑制。另一方面，升高的 GP73 导致 TGF-β1 诱导的 ERK/Akt 信号的上调。在机制上，通过 GP73 过表达诱导的脂筏和 caveolae-1 的上调介导其对 TGF-β1 信号的调节作用。值得注意的是，脂筏的表达在 HCC 肿瘤和表达更高 GP73 的组织中升高，产生更强烈的 Flotillin 染色。我们的结果建立了 GP73 和 TGF-β 信号之间的联系，表明 GP73 可能通过通过脂质筏调节选择性调节 TGF-β 信号来促进 HCC 肿瘤发生。
