Biological Function And Pathogenic Molecular Mechanism Of DDX3X In NKTCL Treatment

PART IBiological function of DDX3 X in NKTCL progression.NK / T-cell lymphoma(NKTCL)is a CD56 positive lymphoid malignancy associated with Epstein-Barr virus(EBV)infection,which occurs in the Asia Pacific region.NKTCL is highly aggressive and often highly resistant to conventional drugs in clinical treatment,and the prognosis of patients is poor.EBV infection is an important factor in the development of NKTCL.After EBV infection,it mostly exists in the host cells in a latent form.Most of the virus proteins do not express,but only a few genes,including: latent membrane proteins: LMP1,LMP2,lmp3,six types of nuclear antigen,and non-coding RNA.EBV is not only the cause of NKTCL,but also an important factor affecting the prognosis of patients.Our previous study also found that ddx3 x,an important RNA helicasegene,had a high frequency of mutation in NKTCL.Ddx3 x and its homologues(ded1p)affect many multicellular biological processes,including transcription,precursor RNA splicing,and m RNA transport translation,etc.,and participate in the regulation of gene expression,especially in the signal regulated by viruses.This project is the continuation of the previous work.From the clinical discovery to the study of structural biology and molecular dynamics model of ddx3 x,we first discussed the function of ddx3 x protein and its mutants on the basis of structure;in order to study the possible regulatory mechanism of ddx3 x and EB virus,we constructed ddx3 x transgenic mice model,HSC Hu mice model modified by ddx3 x mutants.In order to clarify the role of ddx3 x mutation in the pathogenesis of NKTCL and its intrinsic molecular mechanism,we use single-cell transcriptome technology to further discuss the possible damage mechanism of ddx3 x somatic mutation to the host immune system by using the HSC Hu mouse model modified by ddx3 x mutant.It is of great significance to guide clinical practice.PART IIDDX3X mutation and EBV infection in NKTCL Ddx3 x is a multifaceted protein,which shows that it participates in a variety of physiological environments.DDX3 X is highly mutated in NKTCL.Different viruses have evolved complex strategies to isolate and utilize ddx3 x in the virus replication cycle.In NKTCL,EBV and ddx3 x interact and reach a certain balance in host cells.Here we focus on the relationship between the somatic mutation of ddx3 x and the regulation of host cells by EBV.Through the study of NKTCL cell lines with different mutants of ddx3 x,we conclude that ddx3 x,as a tumor suppressor gene,can inhibitthe abnormal activation of p-ERK and NF-KB signals in the host cells of EBV;in the cells with loss of function of ddx3 x protein,EBV activates PKC and p-ERK and NFKB signals downstream of PKC with LMP-1 as the regulatory element in the latent phase of virus.Ddx3 x protein can inhibit the host regulation of virus latent protein by inhibiting the transcription level of PKC,and then inhibit the continuous infection of EB virus and the progression of NKTCL.Here we discuss the molecular mechanism of ddx3 x in EB virus infection model,aiming at clarifying the pathogenesis of NKTCL,screening sensitive and specific molecular markers,which has important guiding significance for the design of targeted therapy.