Epithelial-mesenchymal transition enhances response to oncolytic herpesviral therapy through nectin-1 Journal Article
| Authors: | Chen, C. H.; Chen, W. Y.; Lin, S. F.; Wong, R. J. |
| Article Title: | Epithelial-mesenchymal transition enhances response to oncolytic herpesviral therapy through nectin-1 |
| Abstract: | Cancers exhibiting epithelial-mesenchymal transition (EMT) are associated with aggressive behavior and increased metastatic potential. Therapies that are able to target EMT would have significant clinical value. Nectin-1 is a cell surface herpes simplex virus type 1 (HSV-1) receptor that also forms a component of intercellular adherens junctions, which are typically disrupted in EMT. To explore relationships between HSV-1 sensitivity and EMT, we generated cell lines with a stable EMT phenotype from human follicular thyroid cancer (WRO82-1) through E-cadherin silencing with short hairpin RNA (shEcadWRO). HSV-1 viral attachment and gene expression were both enhanced in shEcadWRO as compared with shControl. Immunoblotting and immunostaining revealed enhanced nectin-1 expression by shEcadWRO. Receptor-blocking assays demonstrated that increased herpesviral entry into shEcadWRO as compared with shControl was mediated predominantly through nectin-1. Colocalization of green fluorescent protein-tagged HSV-1 and tdTomato-tagged nectin-1 confirmed an increase in viral attachment to nectin-1 in shEcadWRO. Cell viability assays demonstrated increased susceptibility of shEcadWRO to HSV-1 oncolysis, and a murine flank tumor model showed significantly enhanced regression of shEcadWRO tumors in response to oncolytic HSV-1 as compared with control tumors. A separate model of EMT induction through transforming growth factor-β stimulation confirmed enhanced HSV-1 susceptibility in Panc1 cells. These results demonstrate that the process of EMT leads to increased herpesviral susceptibility through enhanced cell surface nectin-1 expression, suggesting that cancers exhibiting EMT may be naturally sensitive targets for herpesviral therapy. © 2014, Mary Ann Liebert, Inc. |
| Keywords: | immunohistochemistry; protein expression; treatment response; human cell; nonhuman; protein localization; cell proliferation; mouse; gene expression; tumor volume; transforming growth factor beta; green fluorescent protein; animal experiment; animal model; cytotoxicity; tumor regression; uvomorulin; oncolytic herpes virus; immunoblotting; oncolytic virotherapy; pancreas adenocarcinoma; fluorescence microscopy; gene silencing; virus replication; receptor blocking; cell junction; drug sensitivity; herpes simplex virus 1; short hairpin rna; virus attachment; cell surface; thyroid follicular carcinoma; virus entry; epithelial mesenchymal transition; nectin 1; human; article; adenocarcinoma cell line; cell viability assay |
| Journal Title: | Human Gene Therapy |
| Volume: | 25 |
| Issue: | 6 |
| ISSN: | 1043-0342 |
| Publisher: | Mary Ann Liebert, Inc |
| Date Published: | 2014-06-01 |
| Start Page: | 539 |
| End Page: | 551 |
| Language: | English |
| DOI: | 10.1089/hum.2013.177 |
| PROVIDER: | scopus |
| PMCID: | PMC4064738 |
| PUBMED: | 24568312 |
| DOI/URL: | |
| Notes: | Export Date: 1 August 2014 -- CODEN: HGTHE -- Source: Scopus |
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