Keap1-targeting microRNA-941 protects endometrial cells from oxygen and glucose deprivation-re-oxygenation via activation of Nrf2 signaling
Abstract Background Mimicking ischemia-reperfusion injury, oxygen and glucose deprivation (OGD)-re-oxygenation (OGDR) applied to endometrial cells produces significant oxidative stress and programmed necrosis, which can be inhibited by nuclear-factor-E2-related factor 2 (Nrf2) signaling. MicroRNA (m...
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| Format: | Article |
| Language: | English |
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BMC
2020-02-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12964-020-0526-0 |
| _version_ | 1819158971472150528 |
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| author | Shu-ping Li Wei-nan Cheng Ya Li Hong-bin Xu Hui Han Ping Li Deng-Xia Zhang |
| author_facet | Shu-ping Li Wei-nan Cheng Ya Li Hong-bin Xu Hui Han Ping Li Deng-Xia Zhang |
| author_sort | Shu-ping Li |
| collection | DOAJ |
| description | Abstract Background Mimicking ischemia-reperfusion injury, oxygen and glucose deprivation (OGD)-re-oxygenation (OGDR) applied to endometrial cells produces significant oxidative stress and programmed necrosis, which can be inhibited by nuclear-factor-E2-related factor 2 (Nrf2) signaling. MicroRNA (miRNA)-induced repression of Keap1, a Nrf2 suppressor protein that facilitates Nrf2 degradation, is novel strategy to activate Nrf2 cascade. Methods MicroRNA-941 (miR-941) was exogenously expressed in HESC and primary human endometrial cells, and the Nrf2 pathway examined by Western blotting and real-time quantitative PCR analysis. The endometrial cells were treated with OGDR, cell programmed necrosis and apoptosis were tested. Results MiR-941 is a novel Keap1-targeting miRNA that regulates Nrf2 activity. In T-HESC cells and primary human endometrial cells, ectopic overexpression of miR-941 suppressed Keap1 3′-UTR (untranslated region) expression and downregulated its mRNA/protein expression, leading to activation of the Nrf2 cascade. Conversely, inhibition of miR-941 elevated Keap1 expression and activity in endometrial cells, resulting in suppression of Nrf2 activation. MiR-941 overexpression in endometrial cells attenuated OGDR-induced oxidative stress and programmed necrosis, whereas miR-941 inhibition enhanced oxidative stress and programmed necrosis. MiR-941 overexpression and inhibition were completely ineffective in Keap1−/Nrf2-KO T-HESC cells (using CRISPR/Cas9 strategy). Restoring Keap1 expression, using an UTR-depleted Keap1 construct, abolished miR-941-induced anti-OGDR activity in T-HESC cells. Thus Keap1-Nrf2 cascade activation is required for miR-941-induced endometrial cell protection. Conclusions Targeting Keap1 by miR-941 activates Nrf2 cascade to protect human endometrial cells from OGDR-induced oxidative stress and programmed necrosis. Video Abstract Graphical abstract |
| first_indexed | 2024-12-22T16:33:08Z |
| format | Article |
| id | doaj.art-441c785de2a44cb49ba580e630bad6a8 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-22T16:33:08Z |
| publishDate | 2020-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-441c785de2a44cb49ba580e630bad6a82022-12-21T18:20:01ZengBMCCell Communication and Signaling1478-811X2020-02-0118111310.1186/s12964-020-0526-0Keap1-targeting microRNA-941 protects endometrial cells from oxygen and glucose deprivation-re-oxygenation via activation of Nrf2 signalingShu-ping Li0Wei-nan Cheng1Ya Li2Hong-bin Xu3Hui Han4Ping Li5Deng-Xia Zhang6Obstetrics and Gynecology Department, the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical UniversityDepartment of Orthopedics, The First Affiliated Hospital of Xiamen UniversityThe Central Lab, North District, Suzhou Municipal Hospital affiliated to Nanjing Medical UniversityObstetrics and Gynecology Department, the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical UniversityObstetrics and Gynecology Department, the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical UniversityDepartment of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu UniversityObstetrics and Gynecology Department, the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical UniversityAbstract Background Mimicking ischemia-reperfusion injury, oxygen and glucose deprivation (OGD)-re-oxygenation (OGDR) applied to endometrial cells produces significant oxidative stress and programmed necrosis, which can be inhibited by nuclear-factor-E2-related factor 2 (Nrf2) signaling. MicroRNA (miRNA)-induced repression of Keap1, a Nrf2 suppressor protein that facilitates Nrf2 degradation, is novel strategy to activate Nrf2 cascade. Methods MicroRNA-941 (miR-941) was exogenously expressed in HESC and primary human endometrial cells, and the Nrf2 pathway examined by Western blotting and real-time quantitative PCR analysis. The endometrial cells were treated with OGDR, cell programmed necrosis and apoptosis were tested. Results MiR-941 is a novel Keap1-targeting miRNA that regulates Nrf2 activity. In T-HESC cells and primary human endometrial cells, ectopic overexpression of miR-941 suppressed Keap1 3′-UTR (untranslated region) expression and downregulated its mRNA/protein expression, leading to activation of the Nrf2 cascade. Conversely, inhibition of miR-941 elevated Keap1 expression and activity in endometrial cells, resulting in suppression of Nrf2 activation. MiR-941 overexpression in endometrial cells attenuated OGDR-induced oxidative stress and programmed necrosis, whereas miR-941 inhibition enhanced oxidative stress and programmed necrosis. MiR-941 overexpression and inhibition were completely ineffective in Keap1−/Nrf2-KO T-HESC cells (using CRISPR/Cas9 strategy). Restoring Keap1 expression, using an UTR-depleted Keap1 construct, abolished miR-941-induced anti-OGDR activity in T-HESC cells. Thus Keap1-Nrf2 cascade activation is required for miR-941-induced endometrial cell protection. Conclusions Targeting Keap1 by miR-941 activates Nrf2 cascade to protect human endometrial cells from OGDR-induced oxidative stress and programmed necrosis. Video Abstract Graphical abstracthttp://link.springer.com/article/10.1186/s12964-020-0526-0microRNA-941Nrf2Keap1Endometrial cellsIschemia-reperfusion injury |
| spellingShingle | Shu-ping Li Wei-nan Cheng Ya Li Hong-bin Xu Hui Han Ping Li Deng-Xia Zhang Keap1-targeting microRNA-941 protects endometrial cells from oxygen and glucose deprivation-re-oxygenation via activation of Nrf2 signaling Cell Communication and Signaling microRNA-941 Nrf2 Keap1 Endometrial cells Ischemia-reperfusion injury |
| title | Keap1-targeting microRNA-941 protects endometrial cells from oxygen and glucose deprivation-re-oxygenation via activation of Nrf2 signaling |
| title_full | Keap1-targeting microRNA-941 protects endometrial cells from oxygen and glucose deprivation-re-oxygenation via activation of Nrf2 signaling |
| title_fullStr | Keap1-targeting microRNA-941 protects endometrial cells from oxygen and glucose deprivation-re-oxygenation via activation of Nrf2 signaling |
| title_full_unstemmed | Keap1-targeting microRNA-941 protects endometrial cells from oxygen and glucose deprivation-re-oxygenation via activation of Nrf2 signaling |
| title_short | Keap1-targeting microRNA-941 protects endometrial cells from oxygen and glucose deprivation-re-oxygenation via activation of Nrf2 signaling |
| title_sort | keap1 targeting microrna 941 protects endometrial cells from oxygen and glucose deprivation re oxygenation via activation of nrf2 signaling |
| topic | microRNA-941 Nrf2 Keap1 Endometrial cells Ischemia-reperfusion injury |
| url | http://link.springer.com/article/10.1186/s12964-020-0526-0 |
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