POH1 contributes to hyperactivation of TGF-β signaling and facilitates hepatocellular carcinoma metastasis through deubiquitinating TGF-β receptors and caveolin-1
POH1 contributes to hyperactivation of TGF-β signaling and facilitates hepatocellular carcinoma metastasis through deubiquitinating TGF-β receptors and caveolin-1
复制标题
POH1 有助于 TGF-β 信号的过度激活，并通过去泛素化 TGF-β 受体和 Caveolin-1 促进肝细胞癌转移
DOI：
10.1016/j.ebiom.2019.01.058
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发表时间：
2019-03-01
期刊：
影响因子：
11.1
通讯作者：
Liu, Yongzhong
中科院分区：
文献类型：
--
作者：
Wang, Boshi;Xu, Xiaoli;Liu, Yongzhong
背景：转化生长因子-β信号通路的过度激活与肝细胞癌的发生发展密切相关。方法：通过对在线肝细胞癌数据集的数据挖掘、人肝细胞癌标本的免疫组织化学分析、Spearman相关性分析和生存分析，研究去泛素酶POH1与肝细胞癌中转化生长因子-β信号转导活性和患者预后的关系。用免疫印迹法检测POH1对转化生长因子-β受体(TGFBR1和TGFBR2)泛素化和稳定性以及下游效应分子激活的影响。用多聚肌苷：多胞苷(PolyI：C)处理的Mx-Cre+、poh1f/f小鼠和对照小鼠的原代小鼠肝组织检测转化生长因子-β受体。我们在体外和小鼠体内研究了肝癌细胞的转移相关能力。结果：我们发现POH1是转化生长因子-β信号的关键调节因子，并促进肿瘤转移。对无监督转录组分组的肝细胞癌亚型进行的综合分析显示，POH1的表达与肿瘤中的转化生长因子-β信号活性呈正相关，并与恶性疾病的进展呈正相关。在功能上，POH1增强了转化生长因子-β信号的传递，因此，在体外和体内都促进了肝癌细胞的转移特性。在POH1基因缺陷的小鼠肝细胞中，转化生长因子-β受体的表达严重下调。从机制上讲，POH1去泛素化转化生长因子-β受体和CAV1，从而负向调节溶酶体途径介导的转化生长因子-β受体的周转。结论：POH1异常表达在肝细胞癌转化生长因子-β信号过度激活和侵袭性进展中具有重要的病理学意义。(C)2019年由爱思唯尔出版。这是一篇CC by-NC-ND许可证(http://creativecommons.)下的开放获取文章Org/许可证/by-nc-nd/4.0/)。
Background: Hyper-activation of TGF-beta signaling is critically involved in progression of hepatocellular carcinoma (HCC). However, the events that contribute to the dysregulation of TGF-beta pathway in HCC, especially at the posttranslational level, are not well understood.Methods: Associations of deubiquitinase POH1 with TGF-beta signaling activity and the outcomes of HCC patients were examined by data mining of online HCC datasets, immunohistochemistry analyses using human HCC specimens, spearman correlation and survival analyses. The effects of POH1 on the ubiquitination and stability of the TGF-beta receptors (TGFBR1 and TGFBR2) and the activation of downstreameffectorswere tested by western blotting. Primary mouse liver tissues from polyinosinic: polycytidylic acid (poly I: C)-treated Mx-Cre+, poh1f/f mice and control mice were used to detect the TGF-beta receptors. The metastatic-related capabilities of HCC cells were studied in vitro and in mice.Findings: Herewe show that POH1 is a critical regulator of TGF-beta signaling and promotes tumormetastasis. Integrative analyses of HCC subgroups classified with unsupervised transcriptome clustering of the TGF-beta response, metastatic potential and outcomes, reveal that POH1 expression positively correlateswith activities of TGF-beta signaling in tumors andwithmalignant disease progression. Functionally, POH1 intensifies TGF-beta signaling delivery and, as a consequence, promotes HCC cell metastatic properties both in vitro and in vivo. The expression of the TGF-beta receptors was severely downregulated in POH1-deficient mouse hepatocytes. Mechanistically, POH1 deubiquitinates the TGF-beta receptors and CAV1, therefore negatively regulates lysosome pathway-mediated turnover of TGF-beta receptors.Conclusion: Our study highlights the pathological significance of aberrantly expressed POH1 in TGF-beta signaling hyperactivation and aggressive progression in HCC. (c) 2019 Published by Elsevier B. V. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).