LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner
Abstract Background NONO-TFE3 rearranged renal cell carcinoma (NONO-TFE3 rRCC) is one of a subtype of TFE3 rRCCs with high malignancy and poor prognosis. Compared with clear cell RCC, NONO-TFE3 rRCC shows a preference for mitochondrial respiration. We recently identified that the upregulation of nic...
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-023-02837-4 |
| _version_ | 1827707667805634560 |
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| author | Yi Chen Yanwen Lu Lei Yang Wenliang Ma Yuhan Dong Shuoming Zhou Ning Liu Weidong Gan Dongmei Li |
| author_facet | Yi Chen Yanwen Lu Lei Yang Wenliang Ma Yuhan Dong Shuoming Zhou Ning Liu Weidong Gan Dongmei Li |
| author_sort | Yi Chen |
| collection | DOAJ |
| description | Abstract Background NONO-TFE3 rearranged renal cell carcinoma (NONO-TFE3 rRCC) is one of a subtype of TFE3 rRCCs with high malignancy and poor prognosis. Compared with clear cell RCC, NONO-TFE3 rRCC shows a preference for mitochondrial respiration. We recently identified that the upregulation of nicotinamide ribokinase 2 (NMRK2) was associated with enhanced mitochondrial respiration and tumor progression in TFE3 rRCC. Methods A tumor-bearing mouse model was established to verify the pro-oncogenic effect of NMRK2 on NONO-TFE3 rRCC. Then the expression of NMRK2 RNA and protein was detected in cell lines and patient specimens. The NMRK2 transcripts were Sanger-sequenced and blasted at NCBI website. We constructed dCas13b-HA system to investigate the factors binding with NMRK2 RNA. We also used molecular experiments like RIP-seq, IP-MS, FISH and fluorescence techniques to explore the mechanisms that long non-coding RNA (lncRNA) like NMRK2 mRNA promoted the mitochondrial respiration of NONO-TFE3 rRCC. The efficacy of the combination of shRNA (NMRK2)-lentivirus and metformin on NONO-TFE3 rRCC was assessed by CCK-8 assay. Results In this study, we confirmed that NMRK2 showed transcriptional-translational conflict and functioned as lncRNA like mRNA in the NONO-TFE3 rRCC. Furthermore, we revealed the molecular mechanism that NONO-TFE3 fusion suppressed the translation of NMRK2 mRNA. Most importantly, three major pathways were shown to explain the facilitation effects of lncRNA like NMRK2 mRNA on the mitochondrial respiration of NONO-TFE3 rRCC in an NAD+ kinase-independent manner. Finally, the efficacy of combination of shRNA (NMRK2)-lentivirus and metformin on NONO-TFE3 rRCC was demonstrated to be superior than either agent alone. Conclusions Overall, our data comprehensively demonstrated the mechanisms for the enhanced mitochondrial respiration in NONO-TFE3 rRCC and proposed lncRNA like NMRK2 mRNA as a therapy target for NONO-TFE3 rRCC. Graphical Abstract |
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| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-10T16:50:44Z |
| publishDate | 2023-09-01 |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-593e261d924c4c0e858d664cead23d592023-11-20T11:18:14ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-09-0142112010.1186/s13046-023-02837-4LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent mannerYi Chen0Yanwen Lu1Lei Yang2Wenliang Ma3Yuhan Dong4Shuoming Zhou5Ning Liu6Weidong Gan7Dongmei Li8Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing UniversityDepartment of Urology, Affiliated Drum Tower Hospital of Medical School, Nanjing UniversityDepartment of Clinical Biobank & Institute of Oncology, Affiliated Hospital of Nantong UniversityDepartment of Urology, Affiliated Drum Tower Hospital of Medical School, Nanjing UniversityImmunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing UniversityDepartment of Urology, Affiliated Drum Tower Hospital of Medical School, Nanjing UniversityDepartment of Urology, Nanjing First Hospital, Nanjing Medical UniversityDepartment of Urology, Affiliated Drum Tower Hospital of Medical School, Nanjing UniversityImmunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing UniversityAbstract Background NONO-TFE3 rearranged renal cell carcinoma (NONO-TFE3 rRCC) is one of a subtype of TFE3 rRCCs with high malignancy and poor prognosis. Compared with clear cell RCC, NONO-TFE3 rRCC shows a preference for mitochondrial respiration. We recently identified that the upregulation of nicotinamide ribokinase 2 (NMRK2) was associated with enhanced mitochondrial respiration and tumor progression in TFE3 rRCC. Methods A tumor-bearing mouse model was established to verify the pro-oncogenic effect of NMRK2 on NONO-TFE3 rRCC. Then the expression of NMRK2 RNA and protein was detected in cell lines and patient specimens. The NMRK2 transcripts were Sanger-sequenced and blasted at NCBI website. We constructed dCas13b-HA system to investigate the factors binding with NMRK2 RNA. We also used molecular experiments like RIP-seq, IP-MS, FISH and fluorescence techniques to explore the mechanisms that long non-coding RNA (lncRNA) like NMRK2 mRNA promoted the mitochondrial respiration of NONO-TFE3 rRCC. The efficacy of the combination of shRNA (NMRK2)-lentivirus and metformin on NONO-TFE3 rRCC was assessed by CCK-8 assay. Results In this study, we confirmed that NMRK2 showed transcriptional-translational conflict and functioned as lncRNA like mRNA in the NONO-TFE3 rRCC. Furthermore, we revealed the molecular mechanism that NONO-TFE3 fusion suppressed the translation of NMRK2 mRNA. Most importantly, three major pathways were shown to explain the facilitation effects of lncRNA like NMRK2 mRNA on the mitochondrial respiration of NONO-TFE3 rRCC in an NAD+ kinase-independent manner. Finally, the efficacy of combination of shRNA (NMRK2)-lentivirus and metformin on NONO-TFE3 rRCC was demonstrated to be superior than either agent alone. Conclusions Overall, our data comprehensively demonstrated the mechanisms for the enhanced mitochondrial respiration in NONO-TFE3 rRCC and proposed lncRNA like NMRK2 mRNA as a therapy target for NONO-TFE3 rRCC. Graphical Abstracthttps://doi.org/10.1186/s13046-023-02837-4NONO-TFE3 rRCCMitochondrial respirationTranscriptional-translational conflictlncRNA like mRNANMRK2NAD+ kinase-independent |
| spellingShingle | Yi Chen Yanwen Lu Lei Yang Wenliang Ma Yuhan Dong Shuoming Zhou Ning Liu Weidong Gan Dongmei Li LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner Journal of Experimental & Clinical Cancer Research NONO-TFE3 rRCC Mitochondrial respiration Transcriptional-translational conflict lncRNA like mRNA NMRK2 NAD+ kinase-independent |
| title | LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner |
| title_full | LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner |
| title_fullStr | LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner |
| title_full_unstemmed | LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner |
| title_short | LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner |
| title_sort | lncrna like nmrk2 mrna functions as a key molecular scaffold to enhance mitochondrial respiration of nono tfe3 rearranged renal cell carcinoma in an nad kinase independent manner |
| topic | NONO-TFE3 rRCC Mitochondrial respiration Transcriptional-translational conflict lncRNA like mRNA NMRK2 NAD+ kinase-independent |
| url | https://doi.org/10.1186/s13046-023-02837-4 |
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