Suppression of A-to-I RNA-editing enzyme ADAR1 sensitizes hepatocellular carcinoma cells to oxidative stress through regulating Keap1/Nrf2 pathway
Abstract Background A-to-I RNA editing is an abundant post-transcriptional modification event in hepatocellular carcinoma (HCC). Evidence suggests that adenosine deaminases acting on RNA 1 (ADAR1) correlates to oxidative stress that is a crucial factor of HCC pathogenesis. The present study investig...
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Experimental Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s40164-024-00494-7 |
| _version_ | 1797259414411935744 |
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| author | Houhong Wang Xiaoyu Wei Lu Liu Junfeng Zhang Heng Li |
| author_facet | Houhong Wang Xiaoyu Wei Lu Liu Junfeng Zhang Heng Li |
| author_sort | Houhong Wang |
| collection | DOAJ |
| description | Abstract Background A-to-I RNA editing is an abundant post-transcriptional modification event in hepatocellular carcinoma (HCC). Evidence suggests that adenosine deaminases acting on RNA 1 (ADAR1) correlates to oxidative stress that is a crucial factor of HCC pathogenesis. The present study investigated the effect of ADAR1 on survival and oxidative stress of HCC, and underlying mechanisms. Methods ADAR1 expression was measured in fifty HCC and normal tissues via real-time quantitative PCR, and immunohistochemistry. For stable knockdown or overexpression of ADAR1, adeno-associated virus vectors carrying sh-ADAR1 or ADAR1 overexpression were transfected into HepG2 and SMMC-7721 cells. Transfected cells were exposed to oxidative stress agonist tBHP or sorafenib Bay 43-9006. Cell proliferation, apoptosis, and oxidative stress were measured, and tumor xenograft experiment was implemented. Results ADAR1 was up-regulated in HCC and correlated to unfavorable clinical outcomes. ADAR1 deficiency attenuated proliferation of HCC cells and tumor growth and enhanced apoptosis. Moreover, its loss facilitated intracellular ROS accumulation, and elevated Keap1 and lowered Nrf2 expression. Intracellular GSH content and SOD activity were decreased and MDA content was increased in the absence of ADAR1. The opposite results were observed when ADAR1 was overexpressed. The effects of tBHP and Bay 43–9006 on survival, apoptosis, intracellular ROS accumulation, and Keap1/Nrf2 pathway were further exacerbated by simultaneous inhibition of ADAR1. Conclusions The current study unveils that ADAR1 is required for survival and oxidative stress of HCC cells, and targeting ADAR1 may sensitize HCC cells to oxidative stress via modulating Keap1/Nrf2 pathway. |
| first_indexed | 2024-04-24T23:09:03Z |
| format | Article |
| id | doaj.art-3f2453feeb1140d38db502d5f23e2475 |
| institution | Directory Open Access Journal |
| issn | 2162-3619 |
| language | English |
| last_indexed | 2024-04-24T23:09:03Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj.art-3f2453feeb1140d38db502d5f23e24752024-03-17T12:17:51ZengBMCExperimental Hematology & Oncology2162-36192024-03-0113112010.1186/s40164-024-00494-7Suppression of A-to-I RNA-editing enzyme ADAR1 sensitizes hepatocellular carcinoma cells to oxidative stress through regulating Keap1/Nrf2 pathwayHouhong Wang0Xiaoyu Wei1Lu Liu2Junfeng Zhang3Heng Li4Department of General Surgery, The First Hospital Affiliated to Fuyang Normal UniversityDepartment of Infectious Diseases, Yongchuan Hospital of Chongqing Medical UniversityDepartment of Endocrinology, The Affiliated Nantong Hospital of Shanghai Jiao Tong UniversityDepartment of Radiology, General Hospital of Western Theater Command of PLADepartment of Comprehensive Surgery, Anhui Provincial Cancer Hospital, West District of The First Affiliated Hospital of USTCAbstract Background A-to-I RNA editing is an abundant post-transcriptional modification event in hepatocellular carcinoma (HCC). Evidence suggests that adenosine deaminases acting on RNA 1 (ADAR1) correlates to oxidative stress that is a crucial factor of HCC pathogenesis. The present study investigated the effect of ADAR1 on survival and oxidative stress of HCC, and underlying mechanisms. Methods ADAR1 expression was measured in fifty HCC and normal tissues via real-time quantitative PCR, and immunohistochemistry. For stable knockdown or overexpression of ADAR1, adeno-associated virus vectors carrying sh-ADAR1 or ADAR1 overexpression were transfected into HepG2 and SMMC-7721 cells. Transfected cells were exposed to oxidative stress agonist tBHP or sorafenib Bay 43-9006. Cell proliferation, apoptosis, and oxidative stress were measured, and tumor xenograft experiment was implemented. Results ADAR1 was up-regulated in HCC and correlated to unfavorable clinical outcomes. ADAR1 deficiency attenuated proliferation of HCC cells and tumor growth and enhanced apoptosis. Moreover, its loss facilitated intracellular ROS accumulation, and elevated Keap1 and lowered Nrf2 expression. Intracellular GSH content and SOD activity were decreased and MDA content was increased in the absence of ADAR1. The opposite results were observed when ADAR1 was overexpressed. The effects of tBHP and Bay 43–9006 on survival, apoptosis, intracellular ROS accumulation, and Keap1/Nrf2 pathway were further exacerbated by simultaneous inhibition of ADAR1. Conclusions The current study unveils that ADAR1 is required for survival and oxidative stress of HCC cells, and targeting ADAR1 may sensitize HCC cells to oxidative stress via modulating Keap1/Nrf2 pathway.https://doi.org/10.1186/s40164-024-00494-7ADAR1Hepatocellular carcinomaOxidative stressSurvivalKeap1/Nrf2Reactive oxygen species |
| spellingShingle | Houhong Wang Xiaoyu Wei Lu Liu Junfeng Zhang Heng Li Suppression of A-to-I RNA-editing enzyme ADAR1 sensitizes hepatocellular carcinoma cells to oxidative stress through regulating Keap1/Nrf2 pathway Experimental Hematology & Oncology ADAR1 Hepatocellular carcinoma Oxidative stress Survival Keap1/Nrf2 Reactive oxygen species |
| title | Suppression of A-to-I RNA-editing enzyme ADAR1 sensitizes hepatocellular carcinoma cells to oxidative stress through regulating Keap1/Nrf2 pathway |
| title_full | Suppression of A-to-I RNA-editing enzyme ADAR1 sensitizes hepatocellular carcinoma cells to oxidative stress through regulating Keap1/Nrf2 pathway |
| title_fullStr | Suppression of A-to-I RNA-editing enzyme ADAR1 sensitizes hepatocellular carcinoma cells to oxidative stress through regulating Keap1/Nrf2 pathway |
| title_full_unstemmed | Suppression of A-to-I RNA-editing enzyme ADAR1 sensitizes hepatocellular carcinoma cells to oxidative stress through regulating Keap1/Nrf2 pathway |
| title_short | Suppression of A-to-I RNA-editing enzyme ADAR1 sensitizes hepatocellular carcinoma cells to oxidative stress through regulating Keap1/Nrf2 pathway |
| title_sort | suppression of a to i rna editing enzyme adar1 sensitizes hepatocellular carcinoma cells to oxidative stress through regulating keap1 nrf2 pathway |
| topic | ADAR1 Hepatocellular carcinoma Oxidative stress Survival Keap1/Nrf2 Reactive oxygen species |
| url | https://doi.org/10.1186/s40164-024-00494-7 |
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