Study On The Role And Mechanism Of ECSIT In Triple-negative Breast Cancer And Non-small-cell Lung Cancer

ECSIT(Evolutionarily Conserved Signaling Intermediate in Toll pathways),as a member of the TLRs/IL-1R signaling pathway,is a downstream molecule of TRAF6 protein.After ubiquitination modification,ECSIT activates NF-κB through a cascade of reactions,leading to translocation of NF-κB into the nucleus to regulate gene transcription which has a vital effect in inflammation and innate immune response.Right now,there are no reports about the role of ECSIT in non-small-cell lung cancer(NSCLC)and breast cancer and possible mechanism.Because tumor development is closely related to inflammation and immune response disorders,we assumed that ECSIT might play some important roles in these cancers.Our work has shown that knockdown of ECSIT increased the rate of MDA-MB-231 cell apoptosis.A subcutaneous tumor model of TNBC was established in BALB/c Nu/Nu mice.In vivo results confirmed that knockdown of ECSIT in MDA-MB-231 cells depressed tumorigenicity and metastasis.Mechanistic investigations indicated that knockdown of ECSIT could decrease the expression of p65 and increase p53 protein expression in nuclei.Moreover,we demonstrated that knockdown of p53 could rescue the cell death caused by ECSIT knockdown,which indicated that ECSIT might be involved in human TNBC progression through a p53-dependent pathway.Furthermore,we downloaded the mRNA expression and survival data of ECSIT from 466 NSCLC patients.Through analysis,we found that patients with low ECSIT expression had significantly better survival than those with high.On this basis,a tumor model was established in B6 Rag-/-mice.It was found that knockdown of ECSIT could inhibit the growth of tumor and improve the survival rate only in the NSCLC,but not in triple-negative breast cancer(TNBC).Next,we focused on investigating the effect of ECSIT on tumor development.In vitro assays demonstrated that ECSIT promoted cell proliferation,migration and invasion in TNBC and NSCLC.Knockdown of ECSIT significantly suppressed cell proliferation,migration and invasion.We further found that knockdown of ECSIT promoted the recruitment and activation of macrophages and NK cells only in the NSCLC.Thus,ECSIT participates in tumor progression through innate immunity.In this study,the relationship between ECSIT and tumor was clarified in both aspects of cells and in vivo,which provides a preliminary theoretical basis for using ECSIT alone as a new target protein or in combination with other drug targets to against tumors,and proposes potential new strategies for tumor clinical diagnosis and treatment.