RAD21 Confers Poor Prognosis and Affects Ovarian Cancer Sensitivity to Poly(ADP-Ribose)Polymerase Inhibitors Through DNA Damage Repair
BackgroundPoly(ADP-ribose)polymerase (PARP) inhibitors are a class of molecular-targeted cancer drugs. Synthetic lethality is a phenomenon that renders homologous recombination repair defective cells more sensitive to PARP inhibitors. As a component of the cohesin complex, RAD21 regulates DNA damage...
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| Format: | Article |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.936550/full |
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| author | Rui Gou Rui Gou Xiao Li Xiao Li Hui Dong Hui Dong Yuexin Hu Yuexin Hu Ouxuan Liu Ouxuan Liu Juanjuan Liu Juanjuan Liu Bei Lin Bei Lin |
| author_facet | Rui Gou Rui Gou Xiao Li Xiao Li Hui Dong Hui Dong Yuexin Hu Yuexin Hu Ouxuan Liu Ouxuan Liu Juanjuan Liu Juanjuan Liu Bei Lin Bei Lin |
| author_sort | Rui Gou |
| collection | DOAJ |
| description | BackgroundPoly(ADP-ribose)polymerase (PARP) inhibitors are a class of molecular-targeted cancer drugs. Synthetic lethality is a phenomenon that renders homologous recombination repair defective cells more sensitive to PARP inhibitors. As a component of the cohesin complex, RAD21 regulates DNA damage repair. However, the biological roles of RAD21 in ovarian cancer and their underlying mechanisms remain unclear.MethodsAn immunohistochemical assay was used to validate the expression of RAD21 in ovarian cancer and its correlation with prognosis. The effects of RAD21 were evaluated through Cell Counting Kit-8 (CCK8), wound-healing, and invasion assays in vitro and the tumor growth in vivo. Furthermore, CCK8 assay and immunofluorescence assay were used to detect the effect of RAD21 on cell sensitivity to PARP inhibitors and their mechanism. The pathway changes were detected by Western blotting.ResultsRAD21 was markedly upregulated in ovarian cancer samples. High RAD21 expression was correlated with poor differentiation and poor prognosis in patients with ovarian cancer. Functionally, RAD21 overexpression promoted cancer cell proliferation, migration, and invasion. Moreover, RAD21 knockdown increased the sensitivity of ovarian cancer cells to three kinds of PARP inhibitors by affecting DNA damage repair. In vivo experiments indicated that RAD21 promoted tumor growth. Mechanistically, the overexpression of RAD21 led to increased phosphorylation levels of Akt and mTOR. Blocking the Akt/mTOR signaling pathway reversed RAD21 overexpression-induced cancer progression and drug resistance.ConclusionsRAD21 can serve as a valuable prognostic marker for ovarian cancer and has the potential as a therapeutic target that can expand the utility of PARP inhibitors. |
| first_indexed | 2024-04-13T14:03:30Z |
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| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-13T14:03:30Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-9cd17f5ecd754efd847e9ba2e3cbb9c42022-12-22T02:44:00ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-07-011210.3389/fonc.2022.936550936550RAD21 Confers Poor Prognosis and Affects Ovarian Cancer Sensitivity to Poly(ADP-Ribose)Polymerase Inhibitors Through DNA Damage RepairRui Gou0Rui Gou1Xiao Li2Xiao Li3Hui Dong4Hui Dong5Yuexin Hu6Yuexin Hu7Ouxuan Liu8Ouxuan Liu9Juanjuan Liu10Juanjuan Liu11Bei Lin12Bei Lin13Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, ChinaKey Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, ChinaDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, ChinaKey Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, ChinaDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, ChinaKey Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, ChinaDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, ChinaKey Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, ChinaDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, ChinaKey Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, ChinaDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, ChinaKey Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, ChinaDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, ChinaKey Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, ChinaBackgroundPoly(ADP-ribose)polymerase (PARP) inhibitors are a class of molecular-targeted cancer drugs. Synthetic lethality is a phenomenon that renders homologous recombination repair defective cells more sensitive to PARP inhibitors. As a component of the cohesin complex, RAD21 regulates DNA damage repair. However, the biological roles of RAD21 in ovarian cancer and their underlying mechanisms remain unclear.MethodsAn immunohistochemical assay was used to validate the expression of RAD21 in ovarian cancer and its correlation with prognosis. The effects of RAD21 were evaluated through Cell Counting Kit-8 (CCK8), wound-healing, and invasion assays in vitro and the tumor growth in vivo. Furthermore, CCK8 assay and immunofluorescence assay were used to detect the effect of RAD21 on cell sensitivity to PARP inhibitors and their mechanism. The pathway changes were detected by Western blotting.ResultsRAD21 was markedly upregulated in ovarian cancer samples. High RAD21 expression was correlated with poor differentiation and poor prognosis in patients with ovarian cancer. Functionally, RAD21 overexpression promoted cancer cell proliferation, migration, and invasion. Moreover, RAD21 knockdown increased the sensitivity of ovarian cancer cells to three kinds of PARP inhibitors by affecting DNA damage repair. In vivo experiments indicated that RAD21 promoted tumor growth. Mechanistically, the overexpression of RAD21 led to increased phosphorylation levels of Akt and mTOR. Blocking the Akt/mTOR signaling pathway reversed RAD21 overexpression-induced cancer progression and drug resistance.ConclusionsRAD21 can serve as a valuable prognostic marker for ovarian cancer and has the potential as a therapeutic target that can expand the utility of PARP inhibitors.https://www.frontiersin.org/articles/10.3389/fonc.2022.936550/fullRAD21ovarian cancerPARP inhibitorDNA damage repairprognosis |
| spellingShingle | Rui Gou Rui Gou Xiao Li Xiao Li Hui Dong Hui Dong Yuexin Hu Yuexin Hu Ouxuan Liu Ouxuan Liu Juanjuan Liu Juanjuan Liu Bei Lin Bei Lin RAD21 Confers Poor Prognosis and Affects Ovarian Cancer Sensitivity to Poly(ADP-Ribose)Polymerase Inhibitors Through DNA Damage Repair Frontiers in Oncology RAD21 ovarian cancer PARP inhibitor DNA damage repair prognosis |
| title | RAD21 Confers Poor Prognosis and Affects Ovarian Cancer Sensitivity to Poly(ADP-Ribose)Polymerase Inhibitors Through DNA Damage Repair |
| title_full | RAD21 Confers Poor Prognosis and Affects Ovarian Cancer Sensitivity to Poly(ADP-Ribose)Polymerase Inhibitors Through DNA Damage Repair |
| title_fullStr | RAD21 Confers Poor Prognosis and Affects Ovarian Cancer Sensitivity to Poly(ADP-Ribose)Polymerase Inhibitors Through DNA Damage Repair |
| title_full_unstemmed | RAD21 Confers Poor Prognosis and Affects Ovarian Cancer Sensitivity to Poly(ADP-Ribose)Polymerase Inhibitors Through DNA Damage Repair |
| title_short | RAD21 Confers Poor Prognosis and Affects Ovarian Cancer Sensitivity to Poly(ADP-Ribose)Polymerase Inhibitors Through DNA Damage Repair |
| title_sort | rad21 confers poor prognosis and affects ovarian cancer sensitivity to poly adp ribose polymerase inhibitors through dna damage repair |
| topic | RAD21 ovarian cancer PARP inhibitor DNA damage repair prognosis |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.936550/full |
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