Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers

Lin, Yongcheng; Zhang, Haipeng; Liang, Jiankai; Li, Kai; Zhu, Wenbo; Fu, Liwu; Wang, Fang; Zheng, Xiaoke; Shi, Huijuan; Wu, Sihan; Xiao, Xiao; Chen, Lijun; Tang, Lin; Yan, Min; Yang, Xiaoxiao; Tan, Yaqian; Qiu, Pengxin; Huang, Yijun; Yin, Wei; Su, Xinwen; Hu, Haiyan; Hu, Jun; Gao, Yan

doi:10.1073/pnas.1408759111

Cited by 122 publications

(136 citation statements)

References 45 publications

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…Moreover, data mining of the gene array data in the GEO database found that in the alphavirus M1 susceptible human hepatocellular carcinoma cell line Hep3B, FAT10 was significantly upregulated (332-fold) as compared with the alphavirus M1 resistant human fetal hepatic cell line L-02 (GEO accession number Fig. 1C) (38). In addition, another microarray data demonstrated a 2-fold FAT10 upregulation in ribavirin-resistant HCV-infected cell lines compared with the original ribavirin-sensitive HCV RNA-replicating cell line (GEO accession number GSE60948) (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

FAT10 Is Critical in Influenza A Virus Replication by Inhibiting Type I IFN

Tang

Yang

Liu

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

The H5N1 avian influenza virus causes severe disease and high mortality, making it a major public health concern worldwide. The virus uses the host cellular machinery for several steps of its life cycle. In this report, we observed overexpression of the ubiquitin-like protein FAT10 following live H5N1 virus infection in BALB/c mice and in the human respiratory epithelial cell lines A549 and BEAS-2B. Further experiments demonstrated that FAT10 increased H5N1 virus replication and decreased the viability of infected cells. Total RNA extracted from H5N1 virus–infected cells, but not other H5N1 viral components, upregulated FAT10, and this process was mediated by the retinoic acid–induced protein I-NF-κB signaling pathway. FAT10 knockdown in A549 cells upregulated type I IFN mRNA expression and enhanced STAT1 phosphorylation during live H5N1 virus infection. Taken together, our data suggest that FAT10 was upregulated via retinoic acid–induced protein I and NF-κB during H5N1 avian influenza virus infection. And the upregulated FAT10 promoted H5N1 viral replication by inhibiting type I IFN.

show abstract

Section: Discussionmentioning

confidence: 99%

FAT10 Is Critical in Influenza A Virus Replication by Inhibiting Type I IFN

Tang

Yang

Liu

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The caspase-3/7 flow cytometry assay kit was from Life Technologies (C10427). The strain of M1 virus has been described in our previous research (5,6), and the virus was grown in the Vero cell line. The titer of virus was calculated by median tissue culture infectious dose assay in BHK-21 cell line.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously shown that cancerselective replication underlies the cancer targeting property of M1 (6,15,16). To understand whether the replication of M1 virus is affected by SMCs, we analyzed the effect of SMCs on the replication of M1 virus.…”

Section: C-iap1 and C-iap2 Play Key Roles In The Enhanced Oncolytic Ementioning

confidence: 99%

“…We have previously identified M1, a strain of Getah-like alphavirus isolated from culicine mosquitoes in the Hainan province of China, as an oncolytic virus that induces endoplasmic reticulum (ER) stress-mediated apoptosis in zinc-finger antiviral protein (ZAP)-deficient cancer cells (5,6). Recently, M1 was reported to be nonpathogenic in nonhuman primates after multiple rounds of repeated i.v.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics

Cai

Lin

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Oncolytic virotherapy is a treatment modality that uses native or genetically modified viruses that selectively replicate in and kill tumor cells. Viruses represent a type of pathogen-associated molecular pattern and thereby induce the up-regulation of dozens of cytokines via activating the host innate immune system. Second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs), which antagonize the function of inhibitor of apoptosis proteins (IAPs) and induce apoptosis, sensitize tumor cells to multiple cytokines. Therefore, we sought to determine whether SMCs sensitize tumor cells to cytokines induced by the oncolytic M1 virus, thus enhancing a bystander killing effect. Here, we report that SMCs potentiate the oncolytic effect of M1 in vitro, in vivo, and ex vivo. This strengthened oncolytic efficacy resulted from the enhanced bystander killing effect caused by the M1 virus via cytokine induction. Through a microarray analysis and subsequent validation using recombinant cytokines, we identified IL-8, IL-1A, and TRAIL as the key cytokines in the bystander killing effect. Furthermore, SMCs increased the replication of M1, and the accumulation of virus protein induced irreversible endoplasmic reticulum stress-and c-Jun N-terminal kinase-mediated apoptosis. Nevertheless, the combined treatment with M1 and SMCs had little effect on normal and human primary cells. Because SMCs selectively and significantly enhance the bystander killing effect and the replication of oncolytic virus M1 specifically in cancer cells, this combined treatment may represent a promising therapeutic strategy.oncolytic virus | SMAC mimetics | bystander killing effect

show abstract

“…Besides its antiviral effect, Todorova et al [11] found that ZAP exerts an antitumor effect by binding to cellular RNA to prevent apoptosis induced by tumor necrosis factor-related apoptosis inducing ligand (TRAIL). In our previous study, we found that a decrease of ZAP expression in cancer tissue compared with pericarcinous tissue is common in liver, colon, and bladder cancer [12], suggesting that loss of ZAP may indeed be favorable for the progression of certain cancers. Bioinformatic analysis of the cBioPortal database (http://www.cbioprotal.org) also revealed that HCC exhibits low expression of ZAP mRNA.…”

Section: Introductionmentioning

confidence: 93%

Association of Low Zinc Finger Antiviral Protein Expression with Progression and Poor Survival of Patients with Hepatocellular Carcinoma

Liu

Zhu

et al. 2018

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

Background/Aims: Zinc finger antiviral protein (ZAP) has been reported to be expressed in hepatocellular carcinoma (HCC), and ZAP expression is associated with apoptotic signaling in cancer cells. This study aimed at investigating the expression of ZAP in HCC cells and its significance in clinical pathology. Methods: Real-time quantitative PCR and western blot assays were employed to detect ZAP RNA and protein expression in normal human hepatocytes, HCC cells, and five primary HCC cell lines. Immunohistochemistry was performed to detect ZAP expression in 147 paraffin-embedded HCC tissues and adjacent normal tissues. The clinical significance of ZAP expression was analyzed in tissue samples from patients with or without infection by hepatitis B virus (HBV). Results: ZAP expression in HCC cells and human primary HCC cell lines was significantly lower than that of normal human hepatocytes. Among 147 HCC samples, ZAP expression was lower in HCC tissues than in adjacent normal tissues for 107 (77.0%) samples. In patients with HCC and HBV infection, ZAP expression was related to pathological grade (P < 0.05); in HBV-negative patients with HCC, ZAP expression was associated with tumor size (P < 0.05) and clinical stage (P < 0.05). The overall survival time in patients with low ZAP expression was significantly shorter than survival times of those with high ZAP expression (P < 0.05), especially for patients with moderately to well-differentiated HCC (Grade 1–2) and HCC at stage T1 and T2 (P < 0.05). Cox multivariate analysis showed that ZAP expression was an independent predictor of survival of patients with HCC (P < 0.01). Conclusion: Low ZAP expression is closely associated with disease progression and poor prognosis for patients with HCC.

show abstract

Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers

Cited by 122 publications

References 45 publications

FAT10 Is Critical in Influenza A Virus Replication by Inhibiting Type I IFN

FAT10 Is Critical in Influenza A Virus Replication by Inhibiting Type I IFN

Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics

Association of Low Zinc Finger Antiviral Protein Expression with Progression and Poor Survival of Patients with Hepatocellular Carcinoma

Contact Info

Product

Resources

About