Functional Role Of Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1) In NSCLC

Obgective: Lung cancer is a common malignant disease in the world,particularly in China it represents a leading cause of cancer-related death.Lung cancer falls into the broad categories of non–small cell lung cancers(NSCLC,encompassing lung adenocarcinomas,squamous cell lung carcinomas and large cell carcinomas)and SCLC.Notably,NSCLC accounts for approximately 80%~85% of lung cancers.20% of NSCLC patients can be treated by surgery but even by radical surgery treatment,while 50% of them still have high incidence of recurrence.In recent years,some new targeted therapies for lung cancer have been developed.EIF4G1(eukaryotic translation initiation factor 4 gamma 1)was first isolated as part of the translation initiation factor EIF4 F complex,The function of the complex EIF4 F is to recruit m RNA to ribosomes which is the initial step of protein synthesis.EIF4G1 participates in protein translation by serving as a scaffold and interacting with several other initiation factors.Recent studies have shown that in addition to facilitate the translation of the protein,EIF4G1 also plays important role in cancer pathogenesis and progression.Recent data have found that EIF4G1 is overexpressed in a variety of cancers including nasopharyngeal cancer,squamous cell carcinoma,and breast cancer.EIF4G1 locates on chromosome 3q27,the region is detected in ~50% of lung cancer which having abnormal amplification.Therefore,EIF4G1 may represent a potential tumor biomarker for NSCLC.Until now,no studies have shown that the overexpression of EIF4G1 in NSCLC is related to tumor cell invasion and metastasis,and it remains unclear whether EIF4G1 is involved in the development of NSCLC.The purpose of this study is through establishment of stable EIF4G1 “knock-down” NSCLC cell-lines,to identify the functional role of EIF4G1 in NSCLC and potential therapeutic values.Methods:(1)Using western blotting,we detected the expressional level of EIF4G1 in several NSCLC cell lines and collected tumor tissues,when compared to normal human bronchial epithelial cell line,16 HBE and the respective adjacent normal lung tissue.(2)Using RNAi technology and functional assays,we observed the effects of silencing of EIF4G1 on NSCLC cellular functions including cell proliferation,apoptosis,cell cycle,migration and invasion.(3)By using co-immunoprecipitation and immunofluorescence approaches,we identified the interaction of EIF4G1 and USP10,a negative regulator for EIF4G1 in NSCLC cells.Results:(1)We found that EIF4G1 expression was greatly increased in NSCLC cells and primary tumors.(2)Silencing of EIF4G1 significantly reduced NSCLC cells growth/proliferation,migration,invasion.We also found that silencing of EIF4G1 induced cell apoptosis and G0/G1 cell cycle arrest.(3)We confirmed the interaction of EIF4G1 and USP10 and their co-localization in the cytoplasm of NSCLC cells.(4)We identified USP10 as an EIF4G1 partner protein but negative regulator involved in EIF4G1-mediated functions within NSCLC cells.Conclusions: EIF4G1 expression is significantly up-regulated in NSCLC and has important role in NSCLC pathogenesis and malignant behaviors.EIF4G1 can directly interact with USP10 in NSCLC cell lines,which acts as a partner protein but negative regulator involved in EIF4G1-mediated cellular functions within NSCLC cells.EIF4G1 together with its partner proteins such as USP10 may represent a novel strategy for NSCLC treatment.