Suppr超能文献

盐诱导激酶(SIK1)调节 HCC 进展和 WNT/β-连环蛋白激活。

Salt-inducible Kinase (SIK1) regulates HCC progression and WNT/β-catenin activation.

机构信息

Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China.

Department of General Surgery, Affiliated Baoan Hospital of Southern Medical University, Shenzhen, China.

出版信息

J Hepatol. 2016 May;64(5):1076-1089. doi: 10.1016/j.jhep.2016.01.005. Epub 2016 Jan 14.

Abstract

BACKGROUND & AIMS: In this study, we investigated the role of salt-inducible kinase 1 (SIK1) and its possible mechanisms in human hepatocellular carcinoma (HCC).

METHODS

Immunoprecipitation, immunohistochemistry, luciferase reporter, Chromatin immunoprecipitation, in vitro kinase assays and a mouse model were used to examine the role of SIK1 on the β-catenin signaling pathway.

RESULTS

SIK1 was significantly downregulated in HCC compared with normal controls. Its introduction in HCC cells markedly suppresses epithelial-to-mesenchymal transition (EMT), tumor growth and lung metastasis in xenograft tumor models. The effect of SIK1 on tumor development occurs at least partially through regulation of β-catenin, as evidenced by the fact that SIK1 overexpression leads to repression of β-catenin transcriptional activity, while SIK1 depletion has the opposite effect. Mechanistically, SIK1 phosphorylates the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) at threonine (T)1391, which promotes the association of nuclear receptor corepressor (NCoR)/SMRT with transducin-beta-like protein 1 (TBL1)/transducing-beta-like 1 X-linked receptor 1 (TBLR1) and disrupts the binding of β-catenin to the TBL1/TBLR1 complex, thereby inactivating the Wnt/β-catenin pathway. However, SMRT-T1391A reverses the phenotype of SIK1 and promotes β-catenin transactivation. Twist1 is identified as a critical factor downstream of SIK1/β-catenin axis, and Twist1 knockdown (Twist1(KD)) reverses SIK1(KD)-mediated changes, whereas SIK1(KD)/Twist1(KD) double knockdown cells were less efficient in establishing tumor growth and metastasis than SIK1(KD) cells. The promoter activity of SIK1 were negatively regulated by Twist1, indicating that a double-negative feedback loop exists. Importantly, levels of SIK1 inversely correlate with Twist1 expression in human HCC specimens.

CONCLUSIONS

Our findings highlight the critical roles of SIK1 and its targets in the regulation of HCC development and provides potential new candidates for HCC therapy.

摘要

背景与目的

本研究旨在探讨盐诱导激酶 1(SIK1)在人肝癌(HCC)中的作用及其可能机制。

方法

采用免疫沉淀、免疫组织化学、荧光素酶报告基因、染色质免疫沉淀、体外激酶测定和小鼠模型,研究 SIK1 对β-连环蛋白信号通路的作用。

结果

与正常对照相比,SIK1 在 HCC 中显著下调。在 HCC 细胞中引入 SIK1 可显著抑制上皮-间充质转化(EMT)、肿瘤生长和异种移植肿瘤模型中的肺转移。SIK1 对肿瘤发生的影响至少部分是通过调节β-连环蛋白实现的,这一事实表明,SIK1 的过表达导致β-连环蛋白转录活性的抑制,而 SIK1 的耗竭则产生相反的效果。从机制上讲,SIK1 在丝氨酸(T)1391 处磷酸化视黄酸和甲状腺激素受体沉默介体(SMRT),促进核受体共抑制因子(NCoR)/SMRT 与转导素-β样蛋白 1(TBL1)/转导素-β样 1 X 连锁受体 1(TBLR1)的结合,并破坏β-连环蛋白与 TBL1/TBLR1 复合物的结合,从而使 Wnt/β-连环蛋白通路失活。然而,SMRT-T1391A 逆转了 SIK1 的表型,并促进了β-连环蛋白的反式激活。Twist1 被鉴定为 SIK1/β-连环蛋白轴下游的关键因素,Twist1 敲低(Twist1(KD))逆转了 SIK1(KD)介导的变化,而 SIK1(KD)/Twist1(KD)双敲低细胞在建立肿瘤生长和转移方面的效率低于 SIK1(KD)细胞。SIK1 的启动子活性受到 Twist1 的负调控,表明存在一个双负反馈环。重要的是,在人类 HCC 标本中,SIK1 的水平与 Twist1 的表达呈负相关。

结论

本研究结果强调了 SIK1 及其靶标在调控 HCC 发生中的关键作用,并为 HCC 治疗提供了潜在的新靶点。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验