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FOXA2和SIRT6的协同作用通过抑制ZEB2来抑制肝细胞癌进展。

Coordination of FOXA2 and SIRT6 suppresses the hepatocellular carcinoma progression through ZEB2 inhibition.

作者信息

Liu Jinghua, Yu Zhen, Xiao Yuanyuan, Meng Qiong, Wang Yeying, Chang Wei

机构信息

Department of Gastroenterology and Hepatology, The 4th Affiliated Hospital of Kunming Medical University.

School of Public Health, Kunming Medical University, Kunming, China.

出版信息

Cancer Manag Res. 2018 Mar 1;10:391-402. doi: 10.2147/CMAR.S150552. eCollection 2018.

DOI:10.2147/CMAR.S150552
PMID:29535552
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5836661/
Abstract

BACKGROUND

The Forkhead transcription family member FOXA2 plays a fundamental role in hepatocellular carcinoma (HCC) progression, but the precise interaction factor and molecular regulation of FOXA2 are not fully understood.

OBJECTIVE

In this study, we found that FOXA2 could interact with sirtuin 6 (SIRT6) directly in vivo and in vitro. We explored that the expressions of FOXA2 and SIRT6 were significantly downregulated in human HCC and HCC cell lines.

METHODS

Functionally, cell counting kit-8 assay and Transwell® assay were performed; we demonstrated that the knockdown of FOXA2 and SIRT6 promoted HepG2 cells and Huh7 cells proliferation and invasion in vitro.

RESULTS

Mechanically, using luciferase reporter assay and fast chromatin immunoprecipitation assay, we showed that FOXA2 and SIRT6 regulated the expression of ZEB2 from transcription level. ZEB2 suppression was involved in the anti-oncogenesis effect of FOXA2 and SIRT6. The negative correlation between the expressions of ZEB2 and FOXA2 or SIRT6 was observed in the tissues of HCC patients.

CONCLUSION

Our findings indicated that the coordination function of FOXA2 and SIRT6 played a critical role in HCC progression and may serve as potential drug candidates for HCC.

摘要

背景

叉头转录家族成员FOXA2在肝细胞癌（HCC）进展中起重要作用，但FOXA2确切的相互作用因子和分子调控机制尚未完全明确。

目的

在本研究中，我们发现FOXA2在体内和体外均可直接与沉默调节蛋白6（SIRT6）相互作用。我们还探究了FOXA2和SIRT6在人肝癌组织及肝癌细胞系中的表达均显著下调。

方法

在功能方面，进行了细胞计数试剂盒-8检测和Transwell检测；我们证明，敲低FOXA2和SIRT6可促进HepG2细胞和Huh7细胞在体外的增殖和侵袭。

结果

在机制上，通过荧光素酶报告基因检测和快速染色质免疫沉淀检测，我们发现FOXA2和SIRT6从转录水平调控锌指E盒结合蛋白2（ZEB2）的表达。ZEB2的抑制参与了FOXA2和SIRT6的抗肿瘤作用。在肝癌患者组织中观察到ZEB2与FOXA2或SIRT6表达之间呈负相关。

结论

我们的研究结果表明，FOXA2和SIRT6的协同作用在肝癌进展中起关键作用，可能成为肝癌潜在的候选药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/cd2c9e5b1df6/cmar-10-391Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/6c750ca53998/cmar-10-391Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/c614066673f5/cmar-10-391Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/8630c190beac/cmar-10-391Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/580b9c196fdf/cmar-10-391Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/533d35866f73/cmar-10-391Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/ff6463bf33bf/cmar-10-391Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/cd2c9e5b1df6/cmar-10-391Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/6c750ca53998/cmar-10-391Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/c614066673f5/cmar-10-391Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/8630c190beac/cmar-10-391Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/580b9c196fdf/cmar-10-391Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/533d35866f73/cmar-10-391Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/ff6463bf33bf/cmar-10-391Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec74/5836661/cd2c9e5b1df6/cmar-10-391Fig7.jpg

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