Evaluating a Targeted Cancer Therapy Approach Mediated by RNA trans-Splicing In Vitro and in a Xenograft Model for Epidermolysis Bullosa-Associated Skin Cancer
| Autor: | Katharina Woess, Yuchen Sun, Hanae Morio, Anna Stierschneider, Anna Kaufmann, Stefan Hainzl, Lisa Trattner, Thomas Kocher, Birgit Tockner, Victoria Leb-Reichl, Markus Steiner, Gabriele Brachtl, Andrew P. South, Johann W. Bauer, Julia Reichelt, Tomomi Furihata, Verena Wally, Ulrich Koller, Josefina Piñón Hofbauer, Christina Guttmann-Gruber |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
squamous cell carcinoma
Skin Neoplasms ganciclovir Cell Survival QH301-705.5 RNA Splicing cancer gene therapy Article Catalysis Cell Line Trans-Splicing Inorganic Chemistry Mice Animals Humans epidermolysis bullosa Biology (General) Physical and Theoretical Chemistry QD1-999 Molecular Biology Spectroscopy Organic Chemistry Disease Management herpes simplex virus thymidine kinase Genetic Therapy General Medicine Xenograft Model Antitumor Assays Epidermolysis Bullosa Dystrophica Computer Science Applications Disease Models Animal Chemistry spliceosome mediated RNA trans-splicing Gene Expression Regulation Genetic Loci Ct-SLCO1B3 Disease Susceptibility |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 1; Pages: 575 International Journal of Molecular Sciences, Vol 23, Iss 575, p 575 (2022) International Journal of Molecular Sciences |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms23010575 |
| Popis: | Conventional anti-cancer therapies based on chemo- and/or radiotherapy represent highly effective means to kill cancer cells but lack tumor specificity and, therefore, result in a wide range of iatrogenic effects. A promising approach to overcome this obstacle is spliceosome-mediated RNA trans-splicing (SMaRT), which can be leveraged to target tumor cells while leaving normal cells unharmed. Notably, a previously established RNA trans-splicing molecule (RTM44) showed efficacy and specificity in exchanging the coding sequence of a cancer target gene (Ct-SLCO1B3) with the suicide gene HSV1-thymidine kinase in a colorectal cancer model, thereby rendering tumor cells sensitive to the prodrug ganciclovir (GCV). In the present work, we expand the application of this approach, using the same RTM44 in aggressive skin cancer arising in the rare genetic skin disease recessive dystrophic epidermolysis bullosa (RDEB). Stable expression of RTM44, but not a splicing-deficient control (NC), in RDEB-SCC cells resulted in expression of the expected fusion product at the mRNA and protein level. Importantly, systemic GCV treatment of mice bearing RTM44-expressing cancer cells resulted in a significant reduction in tumor volume and weight compared with controls. Thus, our results demonstrate the applicability of RTM44-mediated targeting of the cancer gene Ct-SLCO1B3 in a different malignancy. |
| Databáze: | OpenAIRE |
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