Genome‐wide profiling of N6‐methyladenosine‐modified pseudogene‐derived long noncoding RNAs reveals the tumour‐promoting and innate immune‐restraining function of RPS15AP12 in ovarian cancer
Abstract Background Pseudogene‐derived lncRNAs are widely dysregulated in cancer. Technological advancements have facilitated the functional characterization of increasing pseudogenes in cancer progression. However, the association between pseudogenes and RNA N6‐methyladenosine (m6A) modification in...
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2025-03-01
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| Online Access: | https://doi.org/10.1002/ctm2.70249 |
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| author | Jie Xu Yifei Ren Jiayi Lu Fengjiang Qin Dan Yang Chunyan Tang Yu Yang Jing Xu Tao Liu Ping Yi |
| author_facet | Jie Xu Yifei Ren Jiayi Lu Fengjiang Qin Dan Yang Chunyan Tang Yu Yang Jing Xu Tao Liu Ping Yi |
| author_sort | Jie Xu |
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| description | Abstract Background Pseudogene‐derived lncRNAs are widely dysregulated in cancer. Technological advancements have facilitated the functional characterization of increasing pseudogenes in cancer progression. However, the association between pseudogenes and RNA N6‐methyladenosine (m6A) modification in cancer, as well as the underlying mechanisms, remains largely unexplored. Methods We analyzed the expression of 12 146 pseudogenes and comprehensively examined the m6A modification of RNAs derived from them and their paralogs. Through integrative analysis of multi‐omics data, we explored the associations between pseudogene dysregulation and m6A, identifying critical pseudogenes involved in HGSOC progression. Tumour promotion role of RPS15AP12 and its cognate parent gene was characterized by cell proliferation, transwell assays, and scratch assays in ovarian cells and xenograft nude mice. RNA decay assays were used to reveal the participation of m6A in decreasement of RPS15AP12 lncRNA stability. Luciferase reporter assays were performed to verify that RPS15AP12 enhances RPS15A expression by competitively binding to miR‐96‐3p. Western blot and phosphorylation assays were performed to investigate the impairment of RPS15AP12 towards the sensors of MAVS (RIG‐I and MDA5), and downstream p‐TBK1 and p‐IRF3. Finally, ELISA assays were performed to explore the regulatory role of RPS15AP12 in IFN‐β expression. Results M6A is distributed across over a thousand pseudogenes, and hypomethylation leads to their upregulation in HGSOC. We identified a processed pseudogene, RPS15AP12, upregulated by FTO‐mediated m6A demethylation. RPS15AP12 enhances the growth ability and metastatic capabilities of ovarian cancer (OC) cells via functioning as a competitive endogenous RNA (ceRNA) for its host gene, RPS15A, through the sequestration of miR‐96‐3p. Importantly, the deletion of RPS15AP12 diminishes the expression of RPS15A, leading to the upregulation of anti‐tumour immune responses by activating RIG‐I and MDA5 and downstream p‐TBK1 and p‐IRF3 as well as IFN‐β levels. Conclusion Our findings expand the understanding of m6A‐modulated pseudogenes in tumour growth and anti‐tumour innate immunity in OC. Key Points Genome‐wide profiling reveals the redistribution of m6A modification on pseudogene‐derived lncRNAs and m6A redistribution‐relevant dysregulation of pseudogenes in HGSOC. RPS15AP12, as a representative processed pseudogene, is up‐regulated by FTO‐mediated demethylation and acts as a miRNA sponge to promote RPS15A expression via competitively binding to miR‐96‐3p. RPS15AP12/RPS15A axis inhibits MAVS sensors (RIG‐I and MDA5) and downstream IFN‐β levels in ovarian cancer. |
| format | Article |
| id | doaj-art-373799297eaa49c8b6bb0f1e2fe0e4ff |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-03-01 |
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| series | Clinical and Translational Medicine |
| spelling | doaj-art-373799297eaa49c8b6bb0f1e2fe0e4ff2025-08-20T03:47:36ZengWileyClinical and Translational Medicine2001-13262025-03-01153n/an/a10.1002/ctm2.70249Genome‐wide profiling of N6‐methyladenosine‐modified pseudogene‐derived long noncoding RNAs reveals the tumour‐promoting and innate immune‐restraining function of RPS15AP12 in ovarian cancerJie Xu0Yifei Ren1Jiayi Lu2Fengjiang Qin3Dan Yang4Chunyan Tang5Yu Yang6Jing Xu7Tao Liu8Ping Yi9Department of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaAbstract Background Pseudogene‐derived lncRNAs are widely dysregulated in cancer. Technological advancements have facilitated the functional characterization of increasing pseudogenes in cancer progression. However, the association between pseudogenes and RNA N6‐methyladenosine (m6A) modification in cancer, as well as the underlying mechanisms, remains largely unexplored. Methods We analyzed the expression of 12 146 pseudogenes and comprehensively examined the m6A modification of RNAs derived from them and their paralogs. Through integrative analysis of multi‐omics data, we explored the associations between pseudogene dysregulation and m6A, identifying critical pseudogenes involved in HGSOC progression. Tumour promotion role of RPS15AP12 and its cognate parent gene was characterized by cell proliferation, transwell assays, and scratch assays in ovarian cells and xenograft nude mice. RNA decay assays were used to reveal the participation of m6A in decreasement of RPS15AP12 lncRNA stability. Luciferase reporter assays were performed to verify that RPS15AP12 enhances RPS15A expression by competitively binding to miR‐96‐3p. Western blot and phosphorylation assays were performed to investigate the impairment of RPS15AP12 towards the sensors of MAVS (RIG‐I and MDA5), and downstream p‐TBK1 and p‐IRF3. Finally, ELISA assays were performed to explore the regulatory role of RPS15AP12 in IFN‐β expression. Results M6A is distributed across over a thousand pseudogenes, and hypomethylation leads to their upregulation in HGSOC. We identified a processed pseudogene, RPS15AP12, upregulated by FTO‐mediated m6A demethylation. RPS15AP12 enhances the growth ability and metastatic capabilities of ovarian cancer (OC) cells via functioning as a competitive endogenous RNA (ceRNA) for its host gene, RPS15A, through the sequestration of miR‐96‐3p. Importantly, the deletion of RPS15AP12 diminishes the expression of RPS15A, leading to the upregulation of anti‐tumour immune responses by activating RIG‐I and MDA5 and downstream p‐TBK1 and p‐IRF3 as well as IFN‐β levels. Conclusion Our findings expand the understanding of m6A‐modulated pseudogenes in tumour growth and anti‐tumour innate immunity in OC. Key Points Genome‐wide profiling reveals the redistribution of m6A modification on pseudogene‐derived lncRNAs and m6A redistribution‐relevant dysregulation of pseudogenes in HGSOC. RPS15AP12, as a representative processed pseudogene, is up‐regulated by FTO‐mediated demethylation and acts as a miRNA sponge to promote RPS15A expression via competitively binding to miR‐96‐3p. RPS15AP12/RPS15A axis inhibits MAVS sensors (RIG‐I and MDA5) and downstream IFN‐β levels in ovarian cancer.https://doi.org/10.1002/ctm2.70249innate immune responsem6AmiRNA spongeovarian cancerpseudogene |
| spellingShingle | Jie Xu Yifei Ren Jiayi Lu Fengjiang Qin Dan Yang Chunyan Tang Yu Yang Jing Xu Tao Liu Ping Yi Genome‐wide profiling of N6‐methyladenosine‐modified pseudogene‐derived long noncoding RNAs reveals the tumour‐promoting and innate immune‐restraining function of RPS15AP12 in ovarian cancer Clinical and Translational Medicine innate immune response m6A miRNA sponge ovarian cancer pseudogene |
| title | Genome‐wide profiling of N6‐methyladenosine‐modified pseudogene‐derived long noncoding RNAs reveals the tumour‐promoting and innate immune‐restraining function of RPS15AP12 in ovarian cancer |
| title_full | Genome‐wide profiling of N6‐methyladenosine‐modified pseudogene‐derived long noncoding RNAs reveals the tumour‐promoting and innate immune‐restraining function of RPS15AP12 in ovarian cancer |
| title_fullStr | Genome‐wide profiling of N6‐methyladenosine‐modified pseudogene‐derived long noncoding RNAs reveals the tumour‐promoting and innate immune‐restraining function of RPS15AP12 in ovarian cancer |
| title_full_unstemmed | Genome‐wide profiling of N6‐methyladenosine‐modified pseudogene‐derived long noncoding RNAs reveals the tumour‐promoting and innate immune‐restraining function of RPS15AP12 in ovarian cancer |
| title_short | Genome‐wide profiling of N6‐methyladenosine‐modified pseudogene‐derived long noncoding RNAs reveals the tumour‐promoting and innate immune‐restraining function of RPS15AP12 in ovarian cancer |
| title_sort | genome wide profiling of n6 methyladenosine modified pseudogene derived long noncoding rnas reveals the tumour promoting and innate immune restraining function of rps15ap12 in ovarian cancer |
| topic | innate immune response m6A miRNA sponge ovarian cancer pseudogene |
| url | https://doi.org/10.1002/ctm2.70249 |
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