Characterization Of The Expression And The Function Of The RNA Binding Protein EIF4G1 And QKI-5

Background: Epithelial ovarian cancer is the most lethal type of malignant tumor in gynecological cancers.It is estimated that there are nearly 52,100 newly diagnosed ovarian cancer cases and about 22,500 cancer deaths in 2015 in China;moreover,ovarian cancer is the fifth leading cause of cancer-related deaths in women in the United States.Statistics show that more than 70% patients were diagnosed at advanced stage,however,the five-year survival rates for patients who are diagnosed with advanced stage disease ovarian cancer range from 18% to 45%.Thus,the discovery of accurate biomarkers and treatment targets associated with the diagnosis,prognosis and treatment of ovarian cancer would be helpful in high-risk patients.RNA-binding proteins(RBPs),as their name implies,are a class of proteins that can directly bind to RNA.RNA-binding proteins are crucial in various cellular processes at the post-transcriptional level.The eukaryotic translation initiation factor 4 gamma,1(eIF4G1),an RNA-binding protein,is a subunit of the eukaryotic translation initiation complex and a necessary protein in the translation of proteins in eukaryotic cells.This protein serves as a scaffold that interacts with numerous initiation factors including PABP,e IF3,and two e IF4 F components(e IF4 E and RNA helicase e IF4A)to ensure the correct formation of the m RNA-ribosome complex,which is a rate-limiting step during the initiation phase of protein synthesis.Its aberrant expression has been discovered in squamous cell lung carcinoma,malignant pleural mesothelioma,multiple myeloma and cervical cancer.Moreover,multidimensional cancer genome analysis and validation have defined the highest abundance isoform QKI-5 of Quaking(QKI),a member of the signal transduction and activation of RNA(STAR)family of RNA-binding proteins,as a novel tumor suppressor in many cancers.QKI regulates the location,stability,and translational efficiency of target m RNA and thus modulates physiological and pathological processes.To the best of our knowledge,many cancer-related genes are targets of QKI-5,including c-fos,p27,and ?-catenin.However,to date,no studies have examined the role of eIF4G1 and QKI-5 in ovarian cancer,which could be meaningful for the diagnosis and prognosis of ovarian cancer.To sum up,we designed this study to investigate the expression,function and the clinicopathological significance of eIF4G1 and QKI-5 in ovarian cancer.Methods: 1.We performed real-time PCR in 40 fresh serous ovarian cancer tissues and 27 normal ovarian surface epithelial cell specimens to examine eIF4G1 and QKI-5 m RNA expression.2.We constructed three tissue array and performed immunohistochemistry(IHC)to detect the expression of eIF4G1 in 134 patients with serous ovarian cancer and 18 normal ovarian tissues.3.The association between eIF4G1 expression and clinicopathologic characteristics was performed by Chisquare' test.Kaplan-Meier method and log-rank test were applied to estimate progression free survival,overall survival and their differences.Multivariate Cox regression(Proportional hazard model)analysis was used for identification of independent prognostic factors.4.QKI-5 expression was target in the ovarian cancer cell lines to assess the influence of overexpression and knockdown of QKI-5 in the cell growth,migration and invasion.Results: 1.The expression of eIF4G1 was quite strong at the m RNA(P=0.0375)and protein(P=0.0007)levels in ovarian cancer tissues.2.Statistical analysis revealed that eIF4G1 expression was significantly correlated with the clinical tumor stage(P=0.0004)and oentum metastasis(P=0.024).3.The results exhibited that the expression of QKI-5 m RNA was down-regulation in the ovarian cancer tissues(P<0.0001).4.Overexpression QKI-5 in ovarian cancer cell Skov3 suppressed the cell growth,migration and invasion;on the contrary,knockdown QKI-5 in the Skov3 cell enchanced the cell growth,migration and invasion.Conclusions:1.These data revealed that eIF4G1 is markedly expressed in ovarian cancer and that the up-regulating of the eIF4G1 protein is significantly associated with an advanced tumor stage.2.Our data exhibited that the expression of QKI-5 was decreased in the ovarian cancer tissues compared with the normal tissues.Besides,the research in vitro indicated that QKI-5 could efficiently inhibit ovarian cancer cell proliferation,migration and invasion,respectively.3.In conclusion,eIF4G1 and QKI-5 may be independent factors that influence ovarian cancer prognosis and thus potential diagnostic and therapeutic targets.