Location: Endemic Poultry Viral Diseases ResearchTitle: Optimization of oncolytic effect of Newcastle disease virus Clone30 by selecting sensitive tumor host and constructing more oncolytic viruses
|LIU, TIANYAN - Northeast Agricultural University|
|ZHANG, YU - Northeast Agricultural University|
|CAO, YUKAI - Northeast Agricultural University|
|JIANG, SHAN - Jiangsu Kanion Pharmaceutical Co, Ltd|
|SUN, RUI - Northeast Agricultural University|
|YIN, JIECHAO - Northeast Agricultural University|
|GAO, ZHENQIU - Jiangsu Kanion Pharmaceutical Co, Ltd|
|REN, GUIPING - Northeast Agricultural University|
|WANG, ZHENZHONG - Jiangsu Kanion Pharmaceutical Co, Ltd|
|SUI, GUANGCHAO - Northeast Forestry University|
|SUN, XU - Northeast Agricultural University|
|SUN, WENYING - Northeast Agricultural University|
|XIAO, WEI - Jiangsu Kanion Pharmaceutical Co, Ltd|
|LI, DESHAN - Northeast Agricultural University|
Submitted to: Gene Therapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/18/2020
Publication Date: 5/15/2020
Citation: Liu, T., Zhang, Y., Cao, Y., Jiang, S., Sun, R., Yin, J., Gao, Z., Ren, G., Wang, Z., Yu, Q., Sui, G., Sun, X., Sun, W., Xiao, W., Li, D. 2020. Optimization of oncolytic effect of Newcastle disease virus Clone30 by selecting sensitive tumor host and constructing more oncolytic viruses. Gene Therapy. https://doi.org/10.1038/s41434-020-0145-9.
Interpretive Summary: Newcastle disease virus (NDV), an avian pathogen, can selectively replicate in tumor cells in mammals and has been used in clinical trials in humans as an anticancer agent. All known NDV strains are belonged to one serotype but classified into three pathotypes with different oncolytic capacities. In this present study, we investigated the susceptibility of cancer cells to infection with different NDV strains and the molecular mechanism responsible for cancer cell susceptibility and oncolytic ability. The results showed that the susceptibility of cancer cells to infection of NDV was depended on the cancer cell types and positively correlated with the fusogenic ability of NDV strains. The chimeric NDVs with the F or F and HN genes derived from the fusogenic NDV Anhinga strain in the NDV Clone30 vaccine strain backbone substantially increased the oncolytic effect when compared to the Clone30 strain. The enhancement of oncolytic effect was most likely resulted from the Anhinga F, or F and HN proteins upregulated the expression of autophagy-related genes, thus promoting the production of syncytia in the susceptible cancer cells. These results suggest that oncolytic effect of the NDV Clone30 strain can be improved by selecting sensitive tumor host and constructing more fusogenic viruses.
Technical Abstract: The direct oncolytic effect of Newcastle disease virus (NDV) depends on the following two aspects: the susceptibility of cancer cells to virus infection and the ability of virus itself to lyse cancer cells. First, we investigate the susceptibility of cancercells to NDV infection, HepG2, MDA-MB-231, and SH-SY5Y cells were susceptible, A549, MCF7, and LoVo cells were less susceptible. To investigate molecular mechanism responsible for cancer cell susceptibility, transcriptome sequencing was carried out. We found that the levels of alpha-sialic acid acyltransferase were upregulated in MDA-MB-231 cells compared with MCF7 cells, and the interferon was downregulated. Second, to optimize the oncolytic capacity of the wild-type rClone30, a series of chimeric viruses rClone30-Anh(HN), rClone30-Anh(F), and rClone30-Anh(HN-F) were constructed by exchanging the HN gene, F gene or both of non-lytic rClone30 strain with lytic strain Anhinga. rClone30-Anh(F) and rClone30-Anh(HN-F) enhanced the oncolytic effect of the rClone30, and this enhancement is more obvious in the susceptible cells. The oncolytic mechanism of rClone30-Anh(F) was analyzed by transcriptome analyses, in comparison with rClone30, rClone30-Anh(F) upregulated the expression of ATG5, Beclin 1, and MAP1LC3B, thus activating autophagy and promoting the production of syncytia. In conclusion, our study provides a strategy to enhance the oncolytic effect of rClone30.