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Inhibition of EPS8L3 suppresses liver cancer progression and enhances efficacy of sorafenib treatment - 18/06/20

Doi : 10.1016/j.biopha.2020.110284 
Bo Chen a, 1, Yan Pan b, 1, Xin Xu a, 1, Fan Wu c, Xuan Zheng a, Si-Ye Chen a, Yu-Ting Zhao a, Zhou Huang a, Shu-Hui Cheng a, Jian-Xiang Liu b, Wei-Hu Wang d, , Ye-Xiong Li a,
a State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, PR China 
b Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, PR China 
c Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, PR China 
d Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, PR China 

Corresponding author at: State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, 100021 PR China.State Key Laboratory of Molecular Oncology and Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC)Beijing100021PR China⁎⁎Corresponding author at: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142 PR China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Department of Radiation OncologyPeking University Cancer Hospital & InstituteBeijing100142PR China

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Abstract

Background

Liver cancer is a devastating disease that has second highest cancer mortality rate worldwide. Although surgical resection or liver transplantation sometimes cures early stage liver cancer, few therapeutic options are available for advanced-stage liver cancer, highlighting the importance of a better understanding of the disease to find novel therapeutic targets.

Methods

Firstly, clinical features of EPS8L3 on liver cancer RNA-seq dataset of The Cancer Genome Atlas (TCGA) database was analyzed, including gene expression levels in tumor tissues in comparison with the normal tissues as well as the patients’ OS. To confirm the candidate genes, we used short hairpin RNA (shRNA) to knock down the gene and quantify the cell proliferation, apoptosis, and migration. Then micro-array analysis was did to investigate the intracellular mechanisms of EPS8L3. Moreover, to gain further insights into the translational value of the findings, we treated the liver cancer cells with Sorafenib after knocking down the candidate gene, in order to interrogate the combinatorial inhibitory effects on cell metabolism.

Results

As a result, by comparing gene expression profiles of normal liver and cancerous tissues, we find that epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3), a gene with unknown function, is upregulated in liver cancer, and is associated with poor prognosis. Further gene set analyses on liver cancer cells revealed that EPS8L3 is pertinent to cell division and proliferation. Indeed, knocking down EPS8L3 inhibits cell proliferation and migration, and triggers apoptosis in vitro. Additionally, when inoculated into mice, EPS8L3 knocked down cells exhibit slower growth rate. Moreover, EPS8L3 expression can substantially increase the efficacy of low dosage of Sorafenib treatment. Furthermore, the results of immunohistochemical staining of 90 paired liver cancer and adjacent normal samples demonstrated high expression of EPS8L3 yields poor prognosis in Chinese liver cancer patients.

Conclusions

Collectively, our results suggest that EPS8L3 has pivotal oncogenic functions in liver cancer and we propose that EPS8L3 could be a potential therapeutic target to treat liver cancer.

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Abbreviations : HCC, TCGA, shRNA, EPS8L3, LIHC, qRT-PCR, kDa

Keywords : Liver cancer, EPS8L3, Cell division, Apoptosis, Invasion, Sorafenib


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© 2020  The Authors. Publicado por Elsevier Masson SAS. Todos los derechos reservados.
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