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VIM-AS1, which is regulated by CpG methylation, cooperates with IGF2BP1 to inhibit tumor aggressiveness via EPHA3 degradation in hepatocellular carcinoma

Ko Je Yeong|Park Jong Hoon|Kim Myung Sup|Chun Kyung-Hee|Han Su-hyang|Jung Sungju|Oh Sumin|Kim Do Yeon|Kang Eunseo|Yoo Kyung Hyun
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2024.12|Experimental and Molecular Medicine|제56권 |pp. 2617-2630|DOI 10.1038/s12276-024-01352-6

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주제분류생화학

초록

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.

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.

참고문헌 (50)

  1. Anand, U., "Cancer chemotherapy and beyond : Current status, drug candidates, associated risks and progress in targeted therapeutics", Genes Dis, 10, pp.1367~1401 (2023)
  2. Autier, P., "Risk factors and biomarkers of life-threatening cancers", Ecancermedicalscience, 9, pp.596~ (2015)
  3. Ceyhan, Y., "Immune cells in residual disease and recurrence", Trends Cancer, 9, pp.554~565 (2023)
  4. Niu, Q., "The role of liver cancer stem cells in hepatocellular carcinoma metastasis", Cancer Biol. Ther, 25, pp.2321768~ (2024)
  5. Yoh, T., "Surgery for Recurrent Hepatocellular Carcinoma : Achieving Longterm Survival", Ann. Surg, 273, pp.792~799 (2021)
  6. Unal, E., "Microvascular invasion in hepatocellular carcinoma", Diagn. Inter. Radio, 22, pp.125~132 (2016)
  7. Zhao, X., "Roles and Molecular Mechanisms of Biomarkers in Hepatocellular Carcinoma with Microvascular Invasion : A Review", J. Clin. Transl. Hepatol, 11, pp.1170~1183 (2023)
  8. Yang, J., "Epigenetic regulation in the tumor microenvironment : molecular mechanisms and therapeutic targets", Signal Transduct. Target Ther, 8, pp.210~ (2023)
  9. Ahmad, A., "Guest Edited Collection : Epigenetics within the tumor microenvironment", Sci. Rep, 12, pp.15089~ (2022)
  10. Xie, Z., "Epigenetic regulation and therapeutic targets in the tumor microenvironment", Mol. Biomed, 4, pp.17~ (2023)
  11. Nagaraju, G. P., "Epigenetics in hepatocellular carcinoma", Semin Cancer Biol, 86, pp.622~632 (2022)
  12. Kim, S. C., "Methylation-sensitive high-resolution melting analysis of the USP44 promoter can detect early-stage hepatocellular carcinoma in blood samples", BMB Rep, 55, pp.553~558 (2022)
  13. Li, R., "Construction and Validation of Novel Diagnostic and Prognostic DNA Methylation Signatures for Hepatocellular Carcinoma", Front Genet, 11, pp.906~ (2020)
  14. Liu, Y., "Epigenetics as a versatile regulator of fibrosis", J. Transl. Med, 21, pp.164~ (2023)
  15. Wang, J., "Long Non-coding RNA 02298 Promotes the Malignancy of HCC by Targeting the miR-28-5p", CCDC6 Pathway, 2024, ~
  16. Zhao, B., "Lnc-CCNH-8 promotes immune escape by up-regulating PD-L1 in hepatocellular carcinoma", Mol. Ther. Nucleic Acids, 35, pp.102125~ (2024)
  17. Liang, W., "The role of long non-coding RNA in hepatocellular carcinoma", Aging (Albany NY), 16, pp.4052~4073 (2024)
  18. Wei, Q., "LncRNA MEG3 Inhibits Tumor Progression by Modulating Macrophage Phenotypic Polarization via miR-145-5p", DAB2 Axis in Hepatocellular Carcinoma, 2023, pp.10, 1019~1035
  19. Zhou, Y., "LncRNA ID2-AS1 suppresses tumor metastasis by activating the HDAC8", ID2 pathway in hepatocellular carcinoma, 2020, pp.469, 399~409
  20. Li, Z., "DNA methylation and gene expression profiles characterize epigenetic regulation of lncRNAs in colon adenocarcinoma", J. Cell Biochem, 121, pp.2406~2415 (2020)
  21. Zheng, G., "Genome-wide DNA methylation analysis by MethylRad and the transcriptome profiles reveal the potential cancer-related lncRNAs in colon cancer", Cancer Med, 9, pp.7601~7612 (2020)
  22. Lu, C., "DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma", Mol. Cancer, 19, pp.28~ (2020)
  23. Wang, Z., "DNA methylation-regulated LINC02587 inhibits ferroptosis and promotes the progression of glioma cells through the CoQ-FSP1 pathway", BMC Cancer, 23, pp.989~ (2023)
  24. Braconi, C., "microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer", Oncogene, 30, pp.4750~4756 (2011)
  25. Caicedo, H. H., "Overcoming barriers to early disease intervention", Nat. Biotechnol, 38, pp.669~673 (2020)
  26. Kim, S. C., "A circulating cell-free DNA methylation signature for the detection of hepatocellular carcinoma", Mol. Cancer, 22, pp.164~ (2023)
  27. Martin, M., "Cutadapt removes adapter sequences from high-throughput sequencing reads", 17(3) (2011)
  28. Langmead, B., "Fast gapped-read alignment with Bowtie 2", Nat. Methods, 9, pp.357~359 (2012)
  29. Heinz, S., "Simple combinations of linSimple combinations of lineagedetermining transcription factors prime cis-regulatory elements required for macrophage and B cell identities", Mol. Cell, 38, pp.576~589 (2010)
  30. Robinson, J. T., "Integrative genomics viewer", Nat. Biotechnol, 29, pp.24~26 (2011)
  31. Li, B., "RSEM : accurate transcript quantification from RNA-Seq data with or without a reference genome", BMC Bioinforma, 12, pp.323~ (2011)
  32. Dobin, A., "STAR : ultrafast universal RNA-seq aligner", Bioinformatics, 29, pp.15~21 (2013)
  33. Love, M. I., "Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2", Genome Biol, 15, pp.550~ (2014)
  34. Subramanian, A., "Gene set enrichment analysis : a knowledge-based approach for interpreting genome-wide expression profiles", Proc. Natl Acad. Sci. USA, 102, pp.15545~15550 (2005)
  35. Gyorffy, B., "Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer", PLoS One, 8, pp.e82241~ (2013)
  36. Sebastian-delaCruz, M., "The Role of lncRNAs in Gene Expression Regulation through mRNA Stabilization", Noncoding RNA, 7 (2021)[DOI]
  37. Bushkin, G. G., "m(6)A modification of a 3’ UTR site reduces RME1 mRNA levels to promote meiosis", Nat. Commun, 10, pp.3414~ (2019)
  38. Wen, T., "The role of m6A epigenetic modifications in tumor coding and noncoding RNA processing", Cell Commun. Signal, 21, pp.355~ (2023)
  39. Pu, J., "IGF2BP2 Promotes Liver Cancer Growth Through an m6A-FEN1-Dependent Mechanism", Front Oncol, 10, pp.578816~ (2020)
  40. Latifkar, A., "IGF2BP2 promotes cancer progression by degrading the RNA transcript encoding a v-ATPase subunit", Proc. Natl Acad. Sci. USA, 119, pp.e2200477119~ (2022)
  41. Sun, H., "The role of cancer-associated fibroblasts in tumorigenesis of gastric cancer", Cell Death Dis, 13, pp.874~ (2022)
  42. Zhang, H., "Define cancer-associated fibroblasts(CAFs)in the tumor microenvironment : new opportunities in cancer immunotherapy and advances in clinical trials", Mol. Cancer, 22, pp.159~ (2023)
  43. Nissen, N. I., "Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology", J. Exp. Clin. Cancer Res, 38, pp.115~ (2019)
  44. Sun, J. G., "lncRNA VIM‑AS1 promotes cell proliferation, metastasis and epithelial‑mesenchymal transition by activating the Wnt", beta‑catenin pathway in gastric cancer, 2020, pp.22, 4567~4578
  45. Rezanejad Bardaji, H., "Long noncoding RNA VIMAS1promotes colorectal cancer progression and metastasis by inducing EMT", Eur. J. Cell Biol, 97, pp.279~288 (2018)
  46. Zhao, X., "Long Noncoding RNA VIM Antisense RNA 1(VIM-AS1)Plays an Important Role in Development of Preeclampsia by Regulation of Epithelial Mesenchymal Transition", Med. Sci. Monit, 25, pp.8306~8314 (2019)
  47. Day, B. W., "EphA3 maintains tumorigenicity and is a therapeutic target in glioblastoma multiforme", Cancer Cell, 23, pp.238~248 (2013)
  48. Parakh, S., "Antibody Drug Conjugates in Glioblastoma - Is There a Future for Them?", Front Oncol, 11, pp.718590~ (2021)
  49. Maher, J., "CAR-Based Immunotherapy of Solid Tumours-A Survey of the Emerging Targets", Cancers (Basel), 15 (2023)[DOI]
  50. Lu, C. Y., "High levels of EphA3 expression are associated with high invasive capacity and poor overall survival in hepatocellular carcinoma", Oncol. Rep, 30, pp.2179~2186 (2013)

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