Research On Antitumor Effect Of Oncolytic Adenovirus Expressing ST13 And TRAIL Against Pancreatic Ductal Adenocarcinoma

Pancreatic cancer(PC)is the most malignant tumor among gastrointestinal tumors,in which pancreatic ductal adenocarcinoma(PDAC)accounts for about 90% of pancreatic cancer.Due to insidious symptoms and high metastasis,the incidence and mortality rate of PDAC has increased gradually in world.Therefore,an effective early-stage predictive indicators and treatment strategies are urgently need to improve the survival rate of PDAC patients.In recent years,oncolytic adenovirus therapy as a novel strategy for cancer therapy that has attracted increasing interest in both research and clinical therapy fields.However,the challenges associated with the therapeutic effect of oncolytic adenovirus alone include security of virus vector and screening of effective antitumor gene.Thus,the selection of safe and efficient viral vectors and therapeutic genes is greatly significance to improve antitumor effects of oncolytic adenovirus in PDAC.In this study,ST13,as a colorectal cancer suppressor gene,was firstly found to be lowly expressed in PDAC and associated with poor prognosis in PDAC patients by immunohistochemical staining assay.In addition,a novel oncolytic adenovirus CD55-ST13-TRAIL was constructed by using genetic engineering technology.This adenovirus was featured with CEA promoter to control E1 A,and E1 B 55 k Da gene deletion in which dual therapeutic gene ST13 and TRAIL was inserted.The Western blot analysis showed that CD55-ST13-TRAIL can efficiently proliferate and promote the expression of ST13 and TRAIL in CEA positive pancreatic cancer cells.Moreover,we detected the effect of CD55-ST13-TRAIL on growth and apoptosis of PDAC cells through MTS,crystal violet staining,flow cytometry and Western blot assay.CD55-ST13-TRAIL exhibited the synergic cell-killing effect compared with CD55-ST13 alone or CD55-TRAIL alone,and inhibits tumor cell proliferation and induced cell apoptosis dependent on Caspase-pathways in PDAC cells.Further xenograft experiments in mice model indicated that CD55-ST13-TRAIL significantly inhibited tumor growth and improved the survival rates of xenograft animal,and had almost no side effect on normal tissues.In conclusion,the findings demonstrated that the oncolytic virotherapy under the control of CEA promoter enables the treatment safety and efficiency to PDAC,which suggests a promising candidate for the treatment of this diseases.