Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growth
Abstract Soft-tissue sarcomas (STSs) are a rare and diverse group of mesenchymal cancers plagued with aggression, poor response to systemic therapy, and high rates of recurrence. Although STSs generally have low mutational burdens, the most commonly mutated genes are tumor suppressors, which frequen...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-36568-5 |
| _version_ | 1797795694552023040 |
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| author | Alexander J. Steiner Yang Zheng Yi Tang |
| author_facet | Alexander J. Steiner Yang Zheng Yi Tang |
| author_sort | Alexander J. Steiner |
| collection | DOAJ |
| description | Abstract Soft-tissue sarcomas (STSs) are a rare and diverse group of mesenchymal cancers plagued with aggression, poor response to systemic therapy, and high rates of recurrence. Although STSs generally have low mutational burdens, the most commonly mutated genes are tumor suppressors, which frequently acquire mutations inducing nonsense-mediated mRNA decay (NMD). This suggests that STS cells may exploit NMD to suppress these anti-cancer genes. To examine the role that the NMD factor SMG7 plays in STS, we developed an inducible knockout mouse model in the Trp53 −/− background. Here, we isolated a subcutaneous STS and identified it as a rhabdomyosarcoma (RMS). We report that knockout of SMG7 significantly inhibited NMD in our RMS cells, which led to the induction of NMD targets GADD45b and the tumor suppressor GAS5. The loss of NMD and upregulation of these anti-cancer genes were concomitant with the loss of RMS cell viability and inhibited tumor growth. Importantly, SMG7 was dispensable for homeostasis in our mouse embryonic fibroblasts and adult mice. Overall, our data show that the loss of SMG7 induces a strong anti-cancer effect both in vitro and in vivo. We present here the first evidence that disrupting SMG7 function may be tolerable and provide a therapeutic benefit for STS treatment. |
| first_indexed | 2024-03-13T03:21:53Z |
| format | Article |
| id | doaj.art-1e686b95da544b71bf6cffaffa920a8a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-13T03:21:53Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-1e686b95da544b71bf6cffaffa920a8a2023-06-25T11:16:52ZengNature PortfolioScientific Reports2045-23222023-06-0113111810.1038/s41598-023-36568-5Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growthAlexander J. Steiner0Yang Zheng1Yi Tang2Department of Regenerative and Cancer Cell Biology, Albany Medical CollegeDepartment of Regenerative and Cancer Cell Biology, Albany Medical CollegeDepartment of Regenerative and Cancer Cell Biology, Albany Medical CollegeAbstract Soft-tissue sarcomas (STSs) are a rare and diverse group of mesenchymal cancers plagued with aggression, poor response to systemic therapy, and high rates of recurrence. Although STSs generally have low mutational burdens, the most commonly mutated genes are tumor suppressors, which frequently acquire mutations inducing nonsense-mediated mRNA decay (NMD). This suggests that STS cells may exploit NMD to suppress these anti-cancer genes. To examine the role that the NMD factor SMG7 plays in STS, we developed an inducible knockout mouse model in the Trp53 −/− background. Here, we isolated a subcutaneous STS and identified it as a rhabdomyosarcoma (RMS). We report that knockout of SMG7 significantly inhibited NMD in our RMS cells, which led to the induction of NMD targets GADD45b and the tumor suppressor GAS5. The loss of NMD and upregulation of these anti-cancer genes were concomitant with the loss of RMS cell viability and inhibited tumor growth. Importantly, SMG7 was dispensable for homeostasis in our mouse embryonic fibroblasts and adult mice. Overall, our data show that the loss of SMG7 induces a strong anti-cancer effect both in vitro and in vivo. We present here the first evidence that disrupting SMG7 function may be tolerable and provide a therapeutic benefit for STS treatment.https://doi.org/10.1038/s41598-023-36568-5 |
| spellingShingle | Alexander J. Steiner Yang Zheng Yi Tang Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growth Scientific Reports |
| title | Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growth |
| title_full | Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growth |
| title_fullStr | Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growth |
| title_full_unstemmed | Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growth |
| title_short | Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growth |
| title_sort | characterization of a rhabdomyosarcoma reveals a critical role for smg7 in cancer cell viability and tumor growth |
| url | https://doi.org/10.1038/s41598-023-36568-5 |
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