Inhibition of EPS8L3 suppresses liver cancer progression and enhances efficacy of sorafenib treatment

Autor: Xin Xu, Yexiong Li, S. Chen, Bo Chen, Xuan Zheng, Jianxiang Liu, Yu-Ting Zhao, Fan Wu, Yan Pan, Weihu Wang, Zhou Huang, Shu-Hui Cheng
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Candidate gene
EPS8L3
medicine.medical_treatment
Apoptosis
Liver transplantation
Small hairpin RNA
0302 clinical medicine
Invasion
Cell Movement
Gene expression
Medicine
Mice
Inbred BALB C
Liver Neoplasms
General Medicine
Hep G2 Cells
Middle Aged
Sorafenib
030220 oncology & carcinogenesis
Female
Liver cancer
medicine.drug
Signal Transduction
Carcinoma
Hepatocellular
Cell division
Down-Regulation
Mice
Nude
Antineoplastic Agents
RM1-950
03 medical and health sciences
Animals
Humans
Neoplasm Invasiveness
Protein Kinase Inhibitors
Adaptor Proteins
Signal Transducing
Cell Proliferation
Pharmacology
business.industry
Cell growth
Cell Cycle Checkpoints
medicine.disease
Xenograft Model Antitumor Assays
030104 developmental biology
Cancer research
Therapeutics. Pharmacology
business
Zdroj: Biomedicine & Pharmacotherapy, Vol 128, Iss, Pp 110284-(2020)
ISSN: 1950-6007
Popis: 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.
Databáze: OpenAIRE
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