The Role Of Potassium Channel EAG1 In The Development Of Hepatocellular Carcinoma And Its Molecular Mechanism

Background:Hepatocellular carcinoma(HCC)is a common malignant tumor,which accounting for the fifth incidence cancer and the third cancer-related mortality worldwide.Only 10%to 20%of hepatocellular carcinomas can be cured by surgery.More than 70%patients recurred after operation in 5 years.Therefore,it is important to explore new pathogenesis and therapeutic targets for the diagnose and treatment of HCC.As one of the potassium channels,ether-a-go-go-1(EAG1)is involved in various physiological processes and plays an important role in the tumorigenesis of many kinds of human cancers.However,the role of EAG1 in hepatocellular carcinoma(HCC)remains unclear and needs to be further explored.Objectives:Quantitative real-time PCR,western blot and immunohistochemistry staining were used to detect EAG1 expressions in HCC tissues.The correlations between EAG1 expression and clinicopathologic features were analyzed.The cell proliferation assay and colony formation assay were applied to evaluate proliferation ability,while trans-well invasion assays were used to evaluate migratory and invasive abilities.For in vivo experiments,subcutaneous xenografted tumors and pulmonary colonization assays were performed.The value of astemizole in the treatment of HCC was evaluated by drug combination experiments.Results:1.EAG1 was overexpressed in HCC tissues and was associated with a poor clinical prognosis.2.In vitro and in vivo experiments showed that EAG1 could promote the proliferation of HCC by inhibiting the ubiquitination of S-phase kinase-associated protein 2(SKP2)and promoting cell cycle progression.3.Our research also revealed that EAG1 could promote the migration and invasion of HCC by promoting cell pseudopod formation.4.Furthermore,we found that astemizole,an EAG1 inhibitor,could promote the anti-tumor effects of doxorubicin on HCC.Conclusion:EAG1 could promote cell proliferation through modulating SKP2 protein level and migration through facilitating pseudopod formation.As EAG1 plays an important role in the progression of HCC,the combined use of astemizole and doxorubicin might be a potential treatment method for HCC.