The Study Of DLK1 As A Target For Liver Cancer Therapeutics

Background:Delta-like 1 homologue(DLK1)is a member of the epidermal growth factor(EGF)-like family of protein.It is widely expressed during embryonic development.Postnatally,however,DLK1 expression is downregulated and becomes restricted to cells of few glands and tissues.Notably,DLK1 expression is upregulated in a wide range of tumor types,including leukemia,neuroblastoma,gliomas,breast cancer,colon cancer,pancreatic cancer and small-cell lung carcinoma,et al.Our previous study indicated that DLK1 is up-regulated in more than half of HCC tissues,and contributes to the proliferation and tumorigenesis of HCC cancer cells.Besides,DLK1~+HCC cells sorted by fluorescence-activated cell sorting manifestchemoresistance and strong tumorigenecity,which are the characteristics of cancer stem/progenitor cells.However,it needs further study to identify the possibility of DLK1 as an effective liver cancer target.In this study,an inducible lentiviral vector expressiong DLK1 sh RNA was constructed to inhibit DLK1 expression.Our data show that inducible vector-mediated DLK1 knockdown suppressed cell proliferation as well as Xenograft tumor expansion.Furthermore,we establish a DEN-induced mouse HCC model,and DLK1 knockdown is mediated by recombinant adenovirus delivering.The results show that the down-regulation of DLK1can retards the tumor initiation and growthin early and late stage of mouse HCC progression.In addition,molecular analysis of DLK1 function indicates markedly down-regulated P27,which is found to regulate the proliferation and differentiation of progenitor cells in Hemopoietic system and mammary gland,by DLK1 knockdown in HCC cells and xenograft tumors.And reveals a possible mechanism of liver cancer progenitor cells regulated by DLK1down-regulation.P27 post-translational modification may play an important role in this process.Finally,we prepare a monoclonal antibody against DLK1,and evaluate the neutralizing effect of antibody on the DLK1 for the first assessment.Taken together,DLK1 knockdown can inhibit tumor initiation and tumor growth of hepatocellular carcinoma,can serve as a potential target of HCC stem/progenitor cell therapeutics.It may be possible to develop DLK1 monoclonal antibody for targeting liver cancer stem/progenitor cells;DLK1 promotes the differentiation of liver cancer progenitor cells possibly via down-regulation of P27expression or post-translational modification alterations;It is possible to develop DLK1 as a therapeutic target for liver cancer monoclonal antibody therapy.