VIM-AS1, which is regulated by CpG methylation, cooperates with IGF2BP1 to inhibit tumor aggressiveness via EPHA3 degradation in hepatocellular carcinoma
Abstract Early tumor recurrence in hepatocellular carcinoma (HCC) remains a challenging area, as the mechanisms involved are not fully understood. While microvascular invasion is linked to early recurrence, established biomarkers for diagnosis and prognostication are lacking. In this study, our obje...
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| Format: | Article |
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Nature Publishing Group
2024-12-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-024-01352-6 |
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| author | Su-hyang Han Je Yeong Ko Sungju Jung Sumin Oh Do Yeon Kim Eunseo Kang Myung Sup Kim Kyung-Hee Chun Kyung Hyun Yoo Jong Hoon Park |
| author_facet | Su-hyang Han Je Yeong Ko Sungju Jung Sumin Oh Do Yeon Kim Eunseo Kang Myung Sup Kim Kyung-Hee Chun Kyung Hyun Yoo Jong Hoon Park |
| author_sort | Su-hyang Han |
| collection | DOAJ |
| description | Abstract Early tumor recurrence in hepatocellular carcinoma (HCC) remains a challenging area, as the mechanisms involved are not fully understood. While microvascular invasion is linked to early recurrence, established biomarkers for diagnosis and prognostication are lacking. In this study, our objective was to identify DNA methylation sites that can predict the outcomes of liver cancer patients and elucidate the molecular mechanisms driving HCC aggressiveness. Using DNA methylome data from HCC patient samples from the CGRC and TCGA databases, we pinpointed hypermethylated CpG sites in HCC. Our analysis revealed that cg02746869 acts as a crucial regulatory site for VIM-AS1 (vimentin antisense RNA1), a 1.8 kb long noncoding RNA. RNA sequencing of HCC cells with manipulated VIM-AS1 expression revealed EPHA3 as a pathogenic target of VIM-AS1, which performs an oncogenic function in HCC. Hypermethylation-induced suppression of VIM-AS1 significantly impacted HCC cell dynamics, particularly impairing motility and invasiveness. Mechanistically, reduced VIM-AS1 expression stabilized EPHA3 mRNA by enhancing the binding of IGF2BP1 to EPHA3 mRNA, leading to increased expression of EPHA3 mRNA and the promotion of HCC progression. In vivo experiments further confirmed that the VIM-AS1‒EPHA3 axis controlled tumor growth and the tumor microenvironment in HCC. These findings suggest that the downregulation of VIM-AS1 due to hypermethylation at cg02746869 increased EPHA3 mRNA expression via a m6A-dependent mechanism to increase HCC aggressiveness. |
| format | Article |
| id | doaj-art-3943ec8434a84bfea666a6cb23b0f6d7 |
| institution | DOAJ |
| issn | 2092-6413 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-3943ec8434a84bfea666a6cb23b0f6d72025-08-20T02:39:49ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132024-12-0156122617263010.1038/s12276-024-01352-6VIM-AS1, which is regulated by CpG methylation, cooperates with IGF2BP1 to inhibit tumor aggressiveness via EPHA3 degradation in hepatocellular carcinomaSu-hyang Han0Je Yeong Ko1Sungju Jung2Sumin Oh3Do Yeon Kim4Eunseo Kang5Myung Sup Kim6Kyung-Hee Chun7Kyung Hyun Yoo8Jong Hoon Park9Laboratory of Biomedical Genomics, Department of Biological Sciences, Sookmyung Women’s UniversityMolecular Medicine Laboratory, Department of Biological Sciences, Sookmyung Women’s UniversityLaboratory of Biomedical Genomics, Department of Biological Sciences, Sookmyung Women’s UniversityLaboratory of Biomedical Genomics, Department of Biological Sciences, Sookmyung Women’s UniversityMolecular Medicine Laboratory, Department of Biological Sciences, Sookmyung Women’s UniversityLaboratory of Biomedical Genomics, Department of Biological Sciences, Sookmyung Women’s UniversityDepartment of Biochemistry and Molecular Biology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of MedicineDepartment of Biochemistry and Molecular Biology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of MedicineLaboratory of Biomedical Genomics, Department of Biological Sciences, Sookmyung Women’s UniversityMolecular Medicine Laboratory, Department of Biological Sciences, Sookmyung Women’s UniversityAbstract Early tumor recurrence in hepatocellular carcinoma (HCC) remains a challenging area, as the mechanisms involved are not fully understood. While microvascular invasion is linked to early recurrence, established biomarkers for diagnosis and prognostication are lacking. In this study, our objective was to identify DNA methylation sites that can predict the outcomes of liver cancer patients and elucidate the molecular mechanisms driving HCC aggressiveness. Using DNA methylome data from HCC patient samples from the CGRC and TCGA databases, we pinpointed hypermethylated CpG sites in HCC. Our analysis revealed that cg02746869 acts as a crucial regulatory site for VIM-AS1 (vimentin antisense RNA1), a 1.8 kb long noncoding RNA. RNA sequencing of HCC cells with manipulated VIM-AS1 expression revealed EPHA3 as a pathogenic target of VIM-AS1, which performs an oncogenic function in HCC. Hypermethylation-induced suppression of VIM-AS1 significantly impacted HCC cell dynamics, particularly impairing motility and invasiveness. Mechanistically, reduced VIM-AS1 expression stabilized EPHA3 mRNA by enhancing the binding of IGF2BP1 to EPHA3 mRNA, leading to increased expression of EPHA3 mRNA and the promotion of HCC progression. In vivo experiments further confirmed that the VIM-AS1‒EPHA3 axis controlled tumor growth and the tumor microenvironment in HCC. These findings suggest that the downregulation of VIM-AS1 due to hypermethylation at cg02746869 increased EPHA3 mRNA expression via a m6A-dependent mechanism to increase HCC aggressiveness.https://doi.org/10.1038/s12276-024-01352-6 |
| spellingShingle | Su-hyang Han Je Yeong Ko Sungju Jung Sumin Oh Do Yeon Kim Eunseo Kang Myung Sup Kim Kyung-Hee Chun Kyung Hyun Yoo Jong Hoon Park VIM-AS1, which is regulated by CpG methylation, cooperates with IGF2BP1 to inhibit tumor aggressiveness via EPHA3 degradation in hepatocellular carcinoma Experimental and Molecular Medicine |
| title | VIM-AS1, which is regulated by CpG methylation, cooperates with IGF2BP1 to inhibit tumor aggressiveness via EPHA3 degradation in hepatocellular carcinoma |
| title_full | VIM-AS1, which is regulated by CpG methylation, cooperates with IGF2BP1 to inhibit tumor aggressiveness via EPHA3 degradation in hepatocellular carcinoma |
| title_fullStr | VIM-AS1, which is regulated by CpG methylation, cooperates with IGF2BP1 to inhibit tumor aggressiveness via EPHA3 degradation in hepatocellular carcinoma |
| title_full_unstemmed | VIM-AS1, which is regulated by CpG methylation, cooperates with IGF2BP1 to inhibit tumor aggressiveness via EPHA3 degradation in hepatocellular carcinoma |
| title_short | VIM-AS1, which is regulated by CpG methylation, cooperates with IGF2BP1 to inhibit tumor aggressiveness via EPHA3 degradation in hepatocellular carcinoma |
| title_sort | vim as1 which is regulated by cpg methylation cooperates with igf2bp1 to inhibit tumor aggressiveness via epha3 degradation in hepatocellular carcinoma |
| url | https://doi.org/10.1038/s12276-024-01352-6 |
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