The Mechanism Study Of Differential Death Of Hepatocarcinoma Cells Induced By Newcastle Disease Virus

As an avian paramyxovirus with oncolytic properties, Newcastle Disease Virus(NDV) can specifically infect and effectively induce oncolysis of many kinds ofmammalian tumor cells, while it has a high safety profile and does not harm to normalcells. Only a few clinical cases have been reported that NDV infections might lead tomild to moderate conjunctivitis, laryngitis and flu-like symptoms, which are allself-limited diseases by recovering quickly. For its ability of selectively eliminatingtumor cells and inducing the stimulation of antitumour activities in immune cells,NDV has become a promising antitumor biological agent in the cancer therapy.Primary liver cancer is one of the worldwide malignancies. The characteristics ofhigh degree of malignancy, rapid progression and poor prognosis, contribute to highmortality of this disease. Surgery is the main treatment with adjuvant therapyincluding chemotherapy, radiation therapy and immunotherapy. However, theeffectiveness of these treatments is not satisfactory because of strong toxic and sideeffects. Furthermore, advanced cancer patients tend to develop drug resistance to theclinic medicine. Therefore, it is urgent to develop new types of personalized methodswith high efficiency and specificity for hepatocarcinoma patients.In this study, we mainly discussed the molecular mechanism of NDV induceddifferential cell death of hepatocarcinoma cells with different differentiation degree.At first, we optimized a NDV culture system using hepatocarcinoma cell lines, thepurified NDV showed the characters of high titers and strong virulent. Then, thepurified virus was applied to infect different liver cancer cell lines and the resultsshowed that the sensitivity to NDV infection is tightly associated with thedifferentiation degree of tested cancer cells. The well-differentiated hepatoma cellsLH86and HLCZ03, which are sensitive to tumor necrosis factor-relatedapoptosis-inducing ligand (TRAIL), are relatively insensitive to NDV infection; whilepoorly-differentiated hepatoma cells Huh7and HLCZ01, which showed drug resistantto TRAIL, are very sensitive to NDV infection and NDV can induce efficientoncolytic effect to these cells at an earlier time point. When exploring the molecularmechanisms, we detected many genes in antiviral pathway and apoptosis pathway.The result showed that although NDV infection can induce high expression ofinterferon beta (IFN-β) in all of the tested cell lines at the late stage. What’s more we found that interferon pathway in these HCC cell lines are functional and can developan immune response against NDV infection. However, only well-differentiated HCCcells can induce increased levels of IFN-β at the early stages of NDV infection, andthis mechanism may help these cells eliminate some virus，thereby slowing down therate of NDV replication to some extent. In addition, we found that the basalexpression level of ISG12a and RIG-I are relatively high in well-differentiated HCCcells, which may play a significant role in the inhibition of NDV replication andmitigate the NDV induced oncolysis.In summary, this study can not only help us to further understand the molecularmechanism of NDV mediated oncolytic effects, but also show new light on the crucialrole of NDV to overcome the TRAIL resistance in human hepatocarcinoma cells.More importantly, it provides a novel strategy for hepartocarcinoma therapy.