The cryptic lncRNA-encoded microprotein TPM3P9 drives oncogenic RNA splicing and tumorigenesis
Abstract Emerging evidence demonstrates that cryptic translation from RNAs previously annotated as noncoding might generate microproteins with oncogenic functions. However, the importance and underlying mechanisms of these microproteins in alternative splicing-driven tumor progression have rarely be...
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| Format: | Article |
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Nature Publishing Group
2025-01-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02128-8 |
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| author | Kun Meng Yuying Li Xiaoyi Yuan Hui-Min Shen Li-Ling Hu Danya Liu Fujin Shi Dandan Zheng Xinyu Shi Nengqiao Wen Yun Cao Yun-Long Pan Qing-Yu He Chris Zhiyi Zhang |
| author_facet | Kun Meng Yuying Li Xiaoyi Yuan Hui-Min Shen Li-Ling Hu Danya Liu Fujin Shi Dandan Zheng Xinyu Shi Nengqiao Wen Yun Cao Yun-Long Pan Qing-Yu He Chris Zhiyi Zhang |
| author_sort | Kun Meng |
| collection | DOAJ |
| description | Abstract Emerging evidence demonstrates that cryptic translation from RNAs previously annotated as noncoding might generate microproteins with oncogenic functions. However, the importance and underlying mechanisms of these microproteins in alternative splicing-driven tumor progression have rarely been studied. Here, we show that the novel protein TPM3P9, encoded by the lncRNA tropomyosin 3 pseudogene 9, exhibits oncogenic activity in clear cell renal cell carcinoma (ccRCC) by enhancing oncogenic RNA splicing. Overexpression of TPM3P9 promotes cell proliferation and tumor growth. Mechanistically, TPM3P9 binds to the RRM1 domain of the splicing factor RBM4 to inhibit RBM4-mediated exon skipping in the transcription factor TCF7L2. This results in increased expression of the oncogenic splice variant TCF7L2-L, which activates NF-κB signaling via its interaction with SAM68 to transcriptionally induce RELB expression. From a clinical perspective, TPM3P9 expression is upregulated in cancer tissues and is significantly correlated with the expression of TCF7L2-L and RELB. High TPM3P9 expression or low RBM4 expression is associated with poor survival in patients with ccRCC. Collectively, our findings functionally and clinically characterize the “noncoding RNA”-derived microprotein TPM3P9 and thus identify potential prognostic and therapeutic factors in renal cancer. |
| format | Article |
| id | doaj-art-1c255317cc95452bb453596720357516 |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-1c255317cc95452bb4535967203575162025-02-02T12:44:33ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-01-0110111710.1038/s41392-025-02128-8The cryptic lncRNA-encoded microprotein TPM3P9 drives oncogenic RNA splicing and tumorigenesisKun Meng0Yuying Li1Xiaoyi Yuan2Hui-Min Shen3Li-Ling Hu4Danya Liu5Fujin Shi6Dandan Zheng7Xinyu Shi8Nengqiao Wen9Yun Cao10Yun-Long Pan11Qing-Yu He12Chris Zhiyi Zhang13MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen UniversityMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityDepartment of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer CenterDepartment of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer CenterThe First Affiliated Hospital of Jinan University, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityAbstract Emerging evidence demonstrates that cryptic translation from RNAs previously annotated as noncoding might generate microproteins with oncogenic functions. However, the importance and underlying mechanisms of these microproteins in alternative splicing-driven tumor progression have rarely been studied. Here, we show that the novel protein TPM3P9, encoded by the lncRNA tropomyosin 3 pseudogene 9, exhibits oncogenic activity in clear cell renal cell carcinoma (ccRCC) by enhancing oncogenic RNA splicing. Overexpression of TPM3P9 promotes cell proliferation and tumor growth. Mechanistically, TPM3P9 binds to the RRM1 domain of the splicing factor RBM4 to inhibit RBM4-mediated exon skipping in the transcription factor TCF7L2. This results in increased expression of the oncogenic splice variant TCF7L2-L, which activates NF-κB signaling via its interaction with SAM68 to transcriptionally induce RELB expression. From a clinical perspective, TPM3P9 expression is upregulated in cancer tissues and is significantly correlated with the expression of TCF7L2-L and RELB. High TPM3P9 expression or low RBM4 expression is associated with poor survival in patients with ccRCC. Collectively, our findings functionally and clinically characterize the “noncoding RNA”-derived microprotein TPM3P9 and thus identify potential prognostic and therapeutic factors in renal cancer.https://doi.org/10.1038/s41392-025-02128-8 |
| spellingShingle | Kun Meng Yuying Li Xiaoyi Yuan Hui-Min Shen Li-Ling Hu Danya Liu Fujin Shi Dandan Zheng Xinyu Shi Nengqiao Wen Yun Cao Yun-Long Pan Qing-Yu He Chris Zhiyi Zhang The cryptic lncRNA-encoded microprotein TPM3P9 drives oncogenic RNA splicing and tumorigenesis Signal Transduction and Targeted Therapy |
| title | The cryptic lncRNA-encoded microprotein TPM3P9 drives oncogenic RNA splicing and tumorigenesis |
| title_full | The cryptic lncRNA-encoded microprotein TPM3P9 drives oncogenic RNA splicing and tumorigenesis |
| title_fullStr | The cryptic lncRNA-encoded microprotein TPM3P9 drives oncogenic RNA splicing and tumorigenesis |
| title_full_unstemmed | The cryptic lncRNA-encoded microprotein TPM3P9 drives oncogenic RNA splicing and tumorigenesis |
| title_short | The cryptic lncRNA-encoded microprotein TPM3P9 drives oncogenic RNA splicing and tumorigenesis |
| title_sort | cryptic lncrna encoded microprotein tpm3p9 drives oncogenic rna splicing and tumorigenesis |
| url | https://doi.org/10.1038/s41392-025-02128-8 |
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