Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cells
The PAX3-FOXO1 fusion gene functions as a transactivator and increases expression of many cancer-related genes. These lead to metastases and other unfavorable outcomes for alveolar rhabdomyosarcoma (ARMS) patients. In order to target ARMS with the PAX3-FOXO1 transactivator, we developed an Oncolytic...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-02-01
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| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523320304897 |
| _version_ | 1819056257350238208 |
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| author | Hideki Yoshida Mizuho Sato-Dahlman Praveensingh Hajeri Kari Jacobsen Lisa Koodie Chikako Yanagiba Ryan Shanley Masato Yamamoto |
| author_facet | Hideki Yoshida Mizuho Sato-Dahlman Praveensingh Hajeri Kari Jacobsen Lisa Koodie Chikako Yanagiba Ryan Shanley Masato Yamamoto |
| author_sort | Hideki Yoshida |
| collection | DOAJ |
| description | The PAX3-FOXO1 fusion gene functions as a transactivator and increases expression of many cancer-related genes. These lead to metastases and other unfavorable outcomes for alveolar rhabdomyosarcoma (ARMS) patients. In order to target ARMS with the PAX3-FOXO1 transactivator, we developed an Oncolytic Adenovirus (OAd) regulated by the myogenin (pMYOG) promoter with a mutation in the Myocyte Enhancer Factor-2 binding site (mMEF2) in this study. The expression of MYOG in the two RMS cell lines (Rh30; PAX3-FOXO1-positive, RD; PAX3-FOXO1-negative) is about 1,000 times higher than normal skeletal muscle cell (SkMC). Ad5/3-pMYOG(S)-mMEF2 (short-length pMYOG-controlled OAd with mMEF2) showed strong replication and cytocidal effect in Rh30, but to a much lesser extent in RD. Ad5/3-pMYOG(S) (pMYOG-controlled OAd with native pMYOG) showed similar effects in RD and Rh30. Neither virus killed SkMC, indicating that Ad5/3-pMYOG(S)-mMEF2 selectively replicates and kills cells with PAX3-FOXO1. Additionally, Ad5/3-pMYOG(S)-mMEF2 showed replication and spread in vitro as well as tumor growth suppression and intratumoral viral spread in vivo, selectively in Rh30 not in RD. Our findings revealed that Ad5/3-pMYOG(S)-mMEF2 shows a promise as a safe and potent therapy to improve treatment in PAX3-FOXO1-positive ARMSs. |
| first_indexed | 2024-12-21T13:20:32Z |
| format | Article |
| id | doaj.art-99f0d7a67fd34a6f99fb7832e972d8bf |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-21T13:20:32Z |
| publishDate | 2021-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-99f0d7a67fd34a6f99fb7832e972d8bf2022-12-21T19:02:35ZengElsevierTranslational Oncology1936-52332021-02-01142100997Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cellsHideki Yoshida0Mizuho Sato-Dahlman1Praveensingh Hajeri2Kari Jacobsen3Lisa Koodie4Chikako Yanagiba5Ryan Shanley6Masato Yamamoto7Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United StatesDepartment of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United StatesDepartment of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United StatesDepartment of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United StatesDepartment of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United StatesDepartment of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United StatesMasonic Cancer Center, Biostatistics Core, University of Minnesota, Minneapolis, MN 55455, United StatesDepartment of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, United States; Corresponding author.The PAX3-FOXO1 fusion gene functions as a transactivator and increases expression of many cancer-related genes. These lead to metastases and other unfavorable outcomes for alveolar rhabdomyosarcoma (ARMS) patients. In order to target ARMS with the PAX3-FOXO1 transactivator, we developed an Oncolytic Adenovirus (OAd) regulated by the myogenin (pMYOG) promoter with a mutation in the Myocyte Enhancer Factor-2 binding site (mMEF2) in this study. The expression of MYOG in the two RMS cell lines (Rh30; PAX3-FOXO1-positive, RD; PAX3-FOXO1-negative) is about 1,000 times higher than normal skeletal muscle cell (SkMC). Ad5/3-pMYOG(S)-mMEF2 (short-length pMYOG-controlled OAd with mMEF2) showed strong replication and cytocidal effect in Rh30, but to a much lesser extent in RD. Ad5/3-pMYOG(S) (pMYOG-controlled OAd with native pMYOG) showed similar effects in RD and Rh30. Neither virus killed SkMC, indicating that Ad5/3-pMYOG(S)-mMEF2 selectively replicates and kills cells with PAX3-FOXO1. Additionally, Ad5/3-pMYOG(S)-mMEF2 showed replication and spread in vitro as well as tumor growth suppression and intratumoral viral spread in vivo, selectively in Rh30 not in RD. Our findings revealed that Ad5/3-pMYOG(S)-mMEF2 shows a promise as a safe and potent therapy to improve treatment in PAX3-FOXO1-positive ARMSs.http://www.sciencedirect.com/science/article/pii/S1936523320304897Child cancerFusion-geneMEF2Soft-tissue sarcomaVirotherapy |
| spellingShingle | Hideki Yoshida Mizuho Sato-Dahlman Praveensingh Hajeri Kari Jacobsen Lisa Koodie Chikako Yanagiba Ryan Shanley Masato Yamamoto Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cells Translational Oncology Child cancer Fusion-gene MEF2 Soft-tissue sarcoma Virotherapy |
| title | Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cells |
| title_full | Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cells |
| title_fullStr | Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cells |
| title_full_unstemmed | Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cells |
| title_short | Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cells |
| title_sort | mutant myogenin promoter controlled oncolytic adenovirus selectively kills pax3 foxo1 positive rhabdomyosarcoma cells |
| topic | Child cancer Fusion-gene MEF2 Soft-tissue sarcoma Virotherapy |
| url | http://www.sciencedirect.com/science/article/pii/S1936523320304897 |
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