A methylation- and immune-related lncRNA signature to predict ovarian cancer outcome and uncover mechanisms of chemoresistance
Abstract Tumor-associated lncRNAs regulated by epigenetic modification switches mediate immune escape and chemoresistance in ovarian cancer (OC). However, the underlying mechanisms and concrete targets have not been systematically elucidated. Here, we discovered that methylation modifications played...
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Journal of Ovarian Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13048-023-01260-9 |
| _version_ | 1827242067866157056 |
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| author | Lu Chen Wujiang Gao Li Lin Chunli Sha Taoqiong Li Qi Chen Hong Wei Meiling Yang Jie Xing Mengxue Zhang Shijie Zhao Wenlin Xu Yuefeng Li Lulu Long Xiaolan Zhu |
| author_facet | Lu Chen Wujiang Gao Li Lin Chunli Sha Taoqiong Li Qi Chen Hong Wei Meiling Yang Jie Xing Mengxue Zhang Shijie Zhao Wenlin Xu Yuefeng Li Lulu Long Xiaolan Zhu |
| author_sort | Lu Chen |
| collection | DOAJ |
| description | Abstract Tumor-associated lncRNAs regulated by epigenetic modification switches mediate immune escape and chemoresistance in ovarian cancer (OC). However, the underlying mechanisms and concrete targets have not been systematically elucidated. Here, we discovered that methylation modifications played a significant role in regulating immune cell infiltration and sensitizing OC to chemotherapy by modulating immune-related lncRNAs (irlncRNAs), which represent tumor immune status. Through deep analysis of the TCGA database, a prognostic risk model incorporating four methylation-related lncRNAs (mrlncRNAs) and irlncRNAs was constructed. Twenty-one mrlncRNA/irlncRNA pairs were identified that were significantly related to the overall survival (OS) of OC patients. Subsequently, we selected four lncRNAs to construct a risk signature predictive of OS and indicative of OC immune infiltration, and verified the robustness of the risk signature in an internal validation set. The risk score was an independent prognostic factor for OC prognosis, which was demonstrated via multifactorial Cox regression analysis and nomogram. Moreover, risk scores were negatively related to the expression of CD274, CTLA4, ICOS, LAG3, PDCD1, and PDCD1LG2 and negatively correlated with CD8+, CD4+, and Treg tumor-infiltrating immune cells. In addition, a high-risk score was associated with a higher IC50 value for cisplatin, which was associated with a significantly worse clinical outcome. Next, a competing endogenous RNA (ceRNA) network and a signaling pathway controlling the infiltration of CD8+ T cells were explored based on the lncRNA model, which suggested a potential therapeutic target for immunotherapy. Overall, this study constructed a prognostic model by pairing mrlncRNAs and irlncRNAs and revealed the critical role of the FTO/RP5-991G20.1/hsa-miR-1976/MEIS1 signaling pathway in regulating immune function and enhancing anticancer therapy. |
| first_indexed | 2024-03-09T14:59:20Z |
| format | Article |
| id | doaj.art-b63f32c3f71044308a8b904196f818de |
| institution | Directory Open Access Journal |
| issn | 1757-2215 |
| language | English |
| last_indexed | 2025-03-21T21:50:29Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Ovarian Research |
| spelling | doaj.art-b63f32c3f71044308a8b904196f818de2024-05-26T11:29:11ZengBMCJournal of Ovarian Research1757-22152023-09-0116112210.1186/s13048-023-01260-9A methylation- and immune-related lncRNA signature to predict ovarian cancer outcome and uncover mechanisms of chemoresistanceLu Chen0Wujiang Gao1Li Lin2Chunli Sha3Taoqiong Li4Qi Chen5Hong Wei6Meiling Yang7Jie Xing8Mengxue Zhang9Shijie Zhao10Wenlin Xu11Yuefeng Li12Lulu Long13Xiaolan Zhu14Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityReproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityReproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityReproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityReproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityReproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityReproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityReproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityReproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityReproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityReproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityReproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityMedical school, Jiangsu UniversityOncology Department, Affiliated People’s Hospital of jiangsu universityReproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu UniversityAbstract Tumor-associated lncRNAs regulated by epigenetic modification switches mediate immune escape and chemoresistance in ovarian cancer (OC). However, the underlying mechanisms and concrete targets have not been systematically elucidated. Here, we discovered that methylation modifications played a significant role in regulating immune cell infiltration and sensitizing OC to chemotherapy by modulating immune-related lncRNAs (irlncRNAs), which represent tumor immune status. Through deep analysis of the TCGA database, a prognostic risk model incorporating four methylation-related lncRNAs (mrlncRNAs) and irlncRNAs was constructed. Twenty-one mrlncRNA/irlncRNA pairs were identified that were significantly related to the overall survival (OS) of OC patients. Subsequently, we selected four lncRNAs to construct a risk signature predictive of OS and indicative of OC immune infiltration, and verified the robustness of the risk signature in an internal validation set. The risk score was an independent prognostic factor for OC prognosis, which was demonstrated via multifactorial Cox regression analysis and nomogram. Moreover, risk scores were negatively related to the expression of CD274, CTLA4, ICOS, LAG3, PDCD1, and PDCD1LG2 and negatively correlated with CD8+, CD4+, and Treg tumor-infiltrating immune cells. In addition, a high-risk score was associated with a higher IC50 value for cisplatin, which was associated with a significantly worse clinical outcome. Next, a competing endogenous RNA (ceRNA) network and a signaling pathway controlling the infiltration of CD8+ T cells were explored based on the lncRNA model, which suggested a potential therapeutic target for immunotherapy. Overall, this study constructed a prognostic model by pairing mrlncRNAs and irlncRNAs and revealed the critical role of the FTO/RP5-991G20.1/hsa-miR-1976/MEIS1 signaling pathway in regulating immune function and enhancing anticancer therapy.https://doi.org/10.1186/s13048-023-01260-9mrlncRNAirlncRNAOCChemoresistanceTumor-infiltrating |
| spellingShingle | Lu Chen Wujiang Gao Li Lin Chunli Sha Taoqiong Li Qi Chen Hong Wei Meiling Yang Jie Xing Mengxue Zhang Shijie Zhao Wenlin Xu Yuefeng Li Lulu Long Xiaolan Zhu A methylation- and immune-related lncRNA signature to predict ovarian cancer outcome and uncover mechanisms of chemoresistance Journal of Ovarian Research mrlncRNA irlncRNA OC Chemoresistance Tumor-infiltrating |
| title | A methylation- and immune-related lncRNA signature to predict ovarian cancer outcome and uncover mechanisms of chemoresistance |
| title_full | A methylation- and immune-related lncRNA signature to predict ovarian cancer outcome and uncover mechanisms of chemoresistance |
| title_fullStr | A methylation- and immune-related lncRNA signature to predict ovarian cancer outcome and uncover mechanisms of chemoresistance |
| title_full_unstemmed | A methylation- and immune-related lncRNA signature to predict ovarian cancer outcome and uncover mechanisms of chemoresistance |
| title_short | A methylation- and immune-related lncRNA signature to predict ovarian cancer outcome and uncover mechanisms of chemoresistance |
| title_sort | methylation and immune related lncrna signature to predict ovarian cancer outcome and uncover mechanisms of chemoresistance |
| topic | mrlncRNA irlncRNA OC Chemoresistance Tumor-infiltrating |
| url | https://doi.org/10.1186/s13048-023-01260-9 |
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