GP73, a novel TGF-beta target gene, provides selective regulation on Smad and non-Smad signaling pathways
GP73, a novel TGF-beta target gene, provides selective regulation on Smad and non-Smad signaling pathways
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GP73 是一种新型 TGF-β 靶基因，可选择性调节 Smad 和非 Smad 信号通路。
DOI：
10.1016/j.bbamcr.2019.01.001
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发表时间：
2019
影响因子：
5.1
通讯作者：
He Xiang
中科院分区：
文献类型：
--
作者：
Yang Xiaoli;Wei Congwen;Liu Ning;Wu Feixiang;Chen Jiankang;Wang Cui;Sun Zhenyu;Wang Yufei;Liu Liping;Zhang Xiaoli;Wang Beihan;Zhang Yanhong;Zhong Hui;Han Yue;He Xiang
通过疾病进展至肝硬化和慢性肝病，来自急性肝炎患者的肝细胞中GP 73表达增加表明进行性组织重塑和纤维化是GP 73上调的驱动力。然而，关于GP 73表达调控及其生物学功能的细节仍然难以捉摸，有待进一步表征。在这项研究中，我们证明GP 73是TGF-β1转录调控的直接靶点。其诱导表达抑制TGF-β-Smad介导的生长抑制。另一方面，升高的GP 73导致由TGF-β1诱导的ERK/Akt信号转导的上调。从机制上讲，GP 73过表达诱导的脂筏和小窝-1上调介导了其对TGF-β1信号转导的调节作用。值得注意的是，在HCC肿瘤中脂筏表达升高，并且具有较高GP 73表达的组织产生更强的Flotilin染色。我们的研究结果建立了GP 73和TGF-β信号之间的联系，表明GP 73可能通过脂筏调节选择性调节TGF-β信号而促进HCC肿瘤的发生。
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.