A Replication-Competent Retroviral Vector Expressing the HERV-W Envelope Glycoprotein is a Potential Tool for Cancer Gene Therapy
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The fusogenic membrane glycoprotein (FMG) derived from the human endogenous retrovirus-W (HERV-W) exhibits fusogenic properties, making it a promising candidate for cancer gene therapy. When cells are transfected with HERV-W FMG, they can fuse with neighboring cells expressing the receptor, resulting in the formation of syncytia. These syncytia eventually undergo cell death within a few days. In addition, it has been observed that an HERV-W env mutant, which is truncated after amino acid 483, displays increased fusogenicity compared to the wild-type HERV-W env. In this study, we observed syncytium formation upon transfection of HeLa and TE671 human cancer cells with plasmids containing the HERV-W 483 gene. To explore the potential of a semi-replicationcompetent retroviral (s-RCR) vector encoding HERV-W 483 for FMG-mediated cancer gene therapy, we developed two replication-defective retroviral vectors: a gag-pol vector encoding HERV-W 483 (MoMLV-HERV-W 483) and an env vector encoding VSV-G (pCLXSN-VSV-G-EGFP). When MoMLVHERV-W 483 and pCLXSN-VSV-G-EGFP were co-transfected into HEK293T cells to produce the s-RCR vector, gradual syncytium formation was observed. However, the titers of the s-RCR virus remained consistently low. To enhance gene transfer efficiency, we constructed an RCR vector encoding HERVW 483 (MoMLV-10A1-HERV-W 483), which demonstrated replication ability in HEK293T cells. Infection of A549 and HT1080 human cancer cell lines with this RCR vector induced syncytium formation and subsequent cell death. Consequently, both the s-RCR vector and RCR encoding HERVW 483 hold promise as valuable tools for cancer gene therapy.
Abstract
The fusogenic membrane glycoprotein (FMG) derived from the human endogenous retrovirus-W (HERV-W) exhibits fusogenic properties, making it a promising candidate for cancer gene therapy. When cells are transfected with HERV-W FMG, they can fuse with neighboring cells expressing the receptor, resulting in the formation of syncytia. These syncytia eventually undergo cell death within a few days. In addition, it has been observed that an HERV-W env mutant, which is truncated after amino acid 483, displays increased fusogenicity compared to the wild-type HERV-W env. In this study, we observed syncytium formation upon transfection of HeLa and TE671 human cancer cells with plasmids containing the HERV-W 483 gene. To explore the potential of a semi-replicationcompetent retroviral (s-RCR) vector encoding HERV-W 483 for FMG-mediated cancer gene therapy, we developed two replication-defective retroviral vectors: a gag-pol vector encoding HERV-W 483 (MoMLV-HERV-W 483) and an env vector encoding VSV-G (pCLXSN-VSV-G-EGFP). When MoMLVHERV-W 483 and pCLXSN-VSV-G-EGFP were co-transfected into HEK293T cells to produce the s-RCR vector, gradual syncytium formation was observed. However, the titers of the s-RCR virus remained consistently low. To enhance gene transfer efficiency, we constructed an RCR vector encoding HERVW 483 (MoMLV-10A1-HERV-W 483), which demonstrated replication ability in HEK293T cells. Infection of A549 and HT1080 human cancer cell lines with this RCR vector induced syncytium formation and subsequent cell death. Consequently, both the s-RCR vector and RCR encoding HERVW 483 hold promise as valuable tools for cancer gene therapy.
참고문헌 (44)
- Frendo JL, "Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation", Mol. Cell Biol, 23, pp.3566~3574 (2003)
- Mi S, "Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis", Nature, 403, pp.785~789 (2000)
- Blond JL, "An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor", J. Virol, 74, pp.3321~3329 (2000)
- Chang C, "Functional characterization of the placental fusogenic membrane protein syncytin", Biol. Reprod, 71, pp.1956~1962 (2004)
- Denner J, "Expression and function of endogenous retroviruses in the placenta", APMIS, 124, pp.31~43 (2016)
- Grandi N, "HERV envelope proteins : physiological role and pathogenic potential in cancer and autoimmunity", Front. Microbiol, 9, pp.462~ (2018)
- Shimizu K, "ASC amino-acid transporter 2(ASCT2)as a novel prognostic marker in non-small cell lung cancer", Br. J. Cancer, 110, pp.2030~2039 (2014)
- Kaira K, "Clinicopathological significance of ASC amino acid transporter-2 expression in pancreatic ductal carcinoma", Histopathology, 66, pp.234~243 (2015)
- Bjerregaard B, "Syncytin is involved in breast cancer-endothelial cell fusions", Cell Mol. Life Sci, 63, pp.1906~1911 (2006)
- Huang W, "Implication of the env gene of the human endogenous retrovirus W family in the expression of BDNF and DRD3 and development of recent-onset schizophrenia", Schizophr. Bull, 37, pp.988~1000 (2011)
- Larsson LI, "Syncytin and cancer cell fusions", Sci. World J, 7, pp.1193~1197 (2007)
- Machnik G, "Porcine endogenous retrovirus(PERV)infection of HEK-293 cell line alters expression of human endogenous retrovirus(HERV-W)sequences", Folia Biol. (Praha), 60, pp.35~46 (2014)
- Lin EH, "Fusogenic membrane glycoproteins induce syncytia formation and death in vitro and in vivo : a potential therapy agent for lung cancer", Cancer Gene. Ther, 17, pp.256~265 (2010)
- Bateman A, "Fusogenic membrane glycoproteins as a novel class of genes for the local and immune-mediated control of tumor growth", Cancer Res, 60, pp.1492~1497 (2000)
- Diaz RM, "A lentiviral vector expressing a fusogenic glycoprotein for cancer gene therapy", Gene Ther, 7, pp.1656~1663 (2000)
- Lee ES, "Construction of replication-competent oncolytic retroviral vectors expressing R peptidetruncated 10A1 envelope glycoprotein", J. Virol. Methods, 268, pp.32~36 (2019)
- Mothes W, "Virus cell-to-cell transmission", J. Virol, 84, pp.8360~8368 (2010)
- Zhang J, "Gene therapy for malignant glioma using Sindbis vectors expressing a fusogenic membrane glycoprotein", J. Gene Med, 6, pp.1082~1091 (2004)
- Cheynet V, "Synthesis, assembly, and processing of the Env ERVWE1", syncytin human endogenous retroviral envelope, 2005, pp.79, 5585~5593
- Drewlo S, "C-Terminal truncations of syncytin-1(ERVWE1 envelope)that increase its fusogenicity", Biol. Chem, 387, pp.1113~1120 (2006)
- Kitao K, "Identification of a post-transcriptional regulatory element in the human endogenous retroviral syncytin-1", J. Gen. Virol, 100, pp.662~668 (2019)
- Lu YC, "Replicating retroviral vectors for oncolytic virotherapy of experimental hepatocellular carcinoma", Oncol. Rep, 28, pp.21~26 (2012)
- Hiraoka K, "Therapeutic efficacy of replication-competent retrovirus vector-mediated suicide gene therapy in a multifocal colorectal cancer metastasis model", Cancer Res, 67, pp.5345~5353 (2007)
- Huang TT, "Intravenous administration of retroviral replicating vector, Toca 511, demonstrates therapeutic efficacy in orthotopic immune-competent mouse glioma model", Hum. Gene Ther, 26, pp.82~93 (2015)
- Solly SK, "Replicative retroviral vectors for cancer gene therapy", Cancer Gene Ther, 10, pp.30~39 (2003)
- Tai CK, "Single-shot, multicycle suicide gene therapy by replication-competent retrovirus vectors achieves long-term survival benefit in experimental glioma", Mol. Ther, 12, pp.842~851 (2005)
- Twitty CG, "Retroviral replicating vectors deliver cytosine deaminase leading to targeted 5-fluorouracil-mediated cytotoxicity in Multiple Human Cancer Types", Hum. Gene Ther. Methods, 27, pp.17~31 (2016)
- Kubo S, "Dual-vector prodrug activator gene therapy using retroviral replicating vectors", Cancer Gene Ther, 26, pp.128~135 (2019)
- Qiao J, "VSV-G pseudotyped, MuLV-based, semireplication-competent retrovirus for cancer treatment", Gene Ther, 13, pp.1457~1470 (2006)
- Trajcevski S, "Characterization of a semi-replicative gene delivery system allowing propagation of complementary defective retroviral vectors", J. Gene Med, 7, pp.276~287 (2005)
- An DS, "Envelope gene of the human endogenous retrovirus HERV-W encodes a functional retrovirus envelope", J. Virol, 75, pp.3488~3489 (2001)
- Logg CR, "Genomic stability of murine leukemia viruses containing insertions at the Env-3' untranslated region boundary", J. Virol, 75, pp.6989~6998 (2001)
- Cheynet V, "Identification of the hASCT2-binding domain of the Env ERVWE1", syncytin-1 fusogenic glycoprotein, 2006, pp.3, 41~
- Chung M, "Induction of syncytia by neuropathogenic murine leukemia viruses depends on receptor density, host cell determinants, and the intrinsic fusion potential of envelope protein", J. Virol, 73, pp.9377~9385 (1999)
- Lavillette D, "The envelope glycoprotein of human endogenous retrovirus type W uses a divergent family of amino acid transporters", cell surface receptors, 2002, pp.76, 6442~6452
- Yu H, "Mutations in 3'-long terminal repeat of HERV-W family in chromosome 7upregulate syncytin-1 expression in urothelial cell carcinoma of the bladder through interacting with c-Myb", Oncogene, 33, pp.3947~3958 (2014)
- Kang BK, "Semi-replication-competent retroviral vectors expressing Gibbon ape leukemia virus fusogenic membrane glycoprotein(GALV FMG)gene for cancer gene therapy", J. Bacteriol. Virol, 50, pp.273~281 (2020)
- Jin SY, "Construction of a replication-competent retroviral vector for expression of the VSV-G envelope glycoprotein for cancer gene therapy", Arch. Virol, 165, pp.1089~1097 (2020)
- Bateman AR, "Viral fusogenic membrane glycoproteins kill solid tumor cells by nonapoptotic mechanisms that promote cross presentation of tumor antigens by dendritic cells", Cancer Res, 62, pp.6566~6578 (2002)
- Higuchi H, "Viral fusogenic membrane glycoprotein expression causes syncytia formation with bioenergetic cell death : implications for gene therapy", Cancer Res, 60, pp.6396~6402 (2000)
- Galanis E, "Use of viral fusogenic membrane glycoproteins as novel therapeutic transgenes in gliomas", Hum. Gene Ther, 12, pp.811~821 (2001)
- Knerr I, "Fusogenic endogenous-retroviral syncytin-1 exerts antiapoptotic functions in staurosporine-challenged CHO cells", Apoptosis, 12, pp.37~43 (2007)
- Knerr I, "Response of HEK293 and CHO cells overexpressing fusogenic syncytin-1 to mitochondrion-mediated apoptosis induced by antimycin A", J. Cell Biochem, 105, pp.766~775 (2008)
- Soygur B, "The role of syncytins in human reproduction and reproductive organ cancers", Reproduction, 152, pp.167~178 (2016)