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Cited by 14Cancer-related molecular mechanisms researchEpigenetics and DNA MethylationRNA modifications and cancer

DNA Methylation Regulates a Set of Long Non-Coding RNAs Compromising Hepatic Identity during Hepatocarcinogenesis

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Recalde, Miriam, Gárate-Rascón, María, Herranz, José María, Elizalde, María, Azkona, María, Unfried, Juan P., Boix, Loreto, Reig, María +6 more·2022·Cancers
DOI 10.3390/cancers14092048PMC PMC9102946
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Abstract

Background: Long noncoding RNAs (lncRNAs) are emerging as key players in cancer, including hepatocellular carcinoma (HCC). Here we identify the mechanism implicated in the HCC inhibition of a set of lncRNAs, and their contribution to the process of hepatocarcinogenesis. Methods and Results: The top-ranked 35 lncRNAs downregulated in HCC (Top35 LNDH) were validated in several human HCC cohorts. We demonstrate that their inhibition is associated with promoter hypermethylation in HCC compared to control tissue, and in HCC human cell lines compared to primary hepatocytes. Moreover, demethylating treatment of HCC human cell lines induced the expression of these lncRNAs. The Top35 LNDH were preferentially expressed in the adult healthy liver compared to other tissues and fetal liver and were induced in well-differentiated HepaRG cells. Remarkably, their knockdown compromised the expression of other hepato-specific genes. Finally, the expression of the Top35 LNDH positively correlates with the grade of tumor differentiation and, more importantly, with a better patient prognosis. Conclusions: Our results demonstrate that the selected Top35 LNDH are not only part of the genes that compose the hepatic differentiated signature but participate in its establishment. Moreover, their downregulation through DNA methylation occurs during the process of hepatocarcinogenesis compromising hepatocellular differentiation and HCC patients’ prognosis.

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  1. [1]Berasain C. Avila M.A. Regulation of Hepatocyte Identity and Quiescence Cell Mol. Life Sci. 2015 72 3831 3851 10.1007/s00018-015-1970-7 26089250 PMC11114060 · DOI
  2. [2]Martins-Filho S.N. Paiva C. Azevedo R.S. Alves V.A.F. Histological Grading of Hepatocellular Carcinoma—A Systematic Review of Literature Front. Med. 2017 4 193 10.3389/fmed.2017.00193 29209611 PMC5701623 · DOI
  3. [3]Sasaki K. Matsuda M. Ohkura Y. Kawamura Y. Inoue M. Hashimoto M. Ikeda K. Kumada H. Watanabe G. The Influence of Histological Differentiation Grade on the Outcome of Liver Resection for Hepatocellular Carcinomas 2 cm or Smaller in Size World J. Surg. 2015 39 1134 1141 10.1007/s00268-014-2806-6 25287916 · DOI
  4. [4]Guerrini G.P. Pinelli D. Benedetto F.D. Marini E. Corno V. Guizzetti M. Aluffi A. Zambelli M. Fagiuoli S. Lucà M.G. Predictive Value of Nodule Size and Differentiation in HCC Recurrence after Liver Transplantation Surg. Oncol. 2016 25 419 428 10.1016/j.suronc.2015.09.003 26403621 · DOI
  5. [5]Harrison P.W. Wright A.E. Mank J.E. The Evolution of Gene Expression and the Transcriptome–Phenotype Relationship Semin. Cell Dev. Biol. 2012 23 222 229 10.1016/j.semcdb.2011.12.004 22210502 PMC3378502 · DOI
  6. [6]Cavalli G. Heard E. Advances in Epigenetics Link Genetics to the Environment and Disease Nature 2019 571 489 499 10.1038/s41586-019-1411-0 31341302 · DOI · Paper page
  7. [7]Brien G.L. Valerio D.G. Armstrong S.A. Exploiting the Epigenome to Control Cancer-Promoting Gene-Expression Programs Cancer Cell 2016 29 464 476 10.1016/j.ccell.2016.03.007 27070701 PMC4889129 · DOI
  8. [9]Meunier L. Hirsch T.Z. Caruso S. Imbeaud S. Bayard Q. Roehrig A. Couchy G. Nault J. Llovet J.M. Blanc J. DNA Methylation Signatures Reveal the Diversity of Processes Remodeling Hepatocellular Carcinoma Methylomes Hepatology 2021 74 816 834 10.1002/hep.31796 33713365 PMC12452108 · DOI
  9. [10]Mallardo M. Poltronieri P. D’Urso O.F. Non-Protein Coding RNA Biomarkers and Differential Expression in Cancers: A Review J. Exp. Clin. Cancer Res. Cr. 2008 27 19 10.1186/1756-9966-27-19 18631387 PMC2490676 · DOI
  10. [11]Unfried J.P. Serrano G. Suárez B. Sangro P. Ferretti V. Prior C. Boix L. Bruix J. Sangro B. Segura V. Identification of Coding and Long Noncoding RNAs Differentially Expressed in Tumors and Preferentially Expressed in Healthy Tissues Cancer Res. 2019 79 5167 5180 10.1158/0008-5472.CAN-19-0400 31387921 · DOI
  11. [12]Ritchie M.E. Phipson B. Wu D. Hu Y. Law C.W. Shi W. Smyth G.K. Limma Powers Differential Expression Analyses for RNA-Sequencing and Microarray Studies Nucleic Acids Res. 2015 43 e47 10.1093/nar/gkv007 25605792 PMC4402510 · DOI · Paper page
  12. [13]Repáraz D. Ruiz M. Llopiz D. Silva L. Vercher E. Aparicio B. Egea J. Tamayo-Uria I. Hervás-Stubbs S. García-Balduz J. Neoantigens as Potential Vaccines in Hepatocellular Carcinoma J. Immunother. Cancer 2022 10 e003978 10.1136/jitc-2021-003978 35193931 PMC9066373 · DOI
  13. [14]Dobin A. Davis C.A. Schlesinger F. Drenkow J. Zaleski C. Jha S. Batut P. Chaisson M. Gingeras T.R. STAR: Ultrafast Universal RNA-Seq Aligner Bioinformatics 2013 29 15 21 10.1093/bioinformatics/bts635 23104886 PMC3530905 · DOI · Paper page
  14. [15]Anders S. Pyl P.T. Huber W. HTSeq—A Python Framework to Work with High-Throughput Sequencing Data Bioinformatics 2015 31 166 169 10.1093/bioinformatics/btu638 25260700 PMC4287950 · DOI · Paper page
  15. [16]Robinson M.D. McCarthy D.J. Smyth G.K. EdgeR: A Bioconductor Package for Differential Expression Analysis of Digital Gene Expression Data Bioinformatics 2010 26 139 140 10.1093/bioinformatics/btp616 19910308 PMC2796818 · DOI · Paper page
  16. [18]Laurent V. Glaise D. Nübel T. Gilot D. Corlu A. Loyer P. Highly Efficient SiRNA and Gene Transfer into Hepatocyte-like HepaRG Cells and Primary Human Hepatocytes: New Means for Drug Metabolism and Toxicity Studies Methods Mol. Biol. 2013 987 295 314 10.1007/978-1-62703-321-3_25 23475687 · DOI
  17. [19]Arechederra M. Daian F. Yim A. Bazai S.K. Richelme S. Dono R. Saurin A.J. Habermann B.H. Maina F. Hypermethylation of Gene Body CpG Islands Predicts High Dosage of Functional Oncogenes in Liver Cancer Nat. Commun. 2018 9 3164 10.1038/s41467-018-05550-5 30089774 PMC6082886 · DOI · Paper page
  18. [20]Ren Y. Wang T.-Y. Anderton L.C. Cao Q. Yang R. LncGSEA: A Versatile Tool to Infer LncRNA Associated Pathways from Large-Scale Cancer Transcriptome Sequencing Data BMC Genom. 2021 22 574 10.1186/s12864-021-07900-y PMC8314497 34315441 · DOI
  19. [21]Yang Y. Chen L. Gu J. Zhang H. Yuan J. Lian Q. Lv G. Wang S. Wu Y. Yang Y.-C.T. Recurrently Deregulated LncRNAs in Hepatocellular Carcinoma Nat. Commun. 2017 8 14421 10.1038/ncomms14421 28194035 PMC5316832 · DOI
  20. [22]Esteller M. Epigenetic Changes in Cancer F1000 Biol. Rep. 2011 3 9 10.3410/B3-9 21655338 PMC3100810 · DOI
  21. [23]Jones P.A. Functions of DNA Methylation: Islands, Start Sites, Gene Bodies and Beyond Nat. Rev. Genet. 2012 13 484 492 10.1038/nrg3230 22641018 · DOI · Paper page
  22. [24]Zhi H. Li X. Wang P. Gao Y. Gao B. Zhou D. Zhang Y. Guo M. Yue M. Shen W. Lnc2Meth: A Manually Curated Database of Regulatory Relationships between Long Non-Coding RNAs and DNA Methylation Associated with Human Disease Nucleic Acids Res. 2018 46 D133 D138 10.1093/nar/gkx985 29069510 PMC5753220 · DOI
  23. [25]Gailhouste L. Liew L.C. Yasukawa K. Hatada I. Tanaka Y. Nakagama H. Ochiya T. Differentiation Therapy by Epigenetic Reconditioning Exerts Antitumor Effects on Liver Cancer Cells Mol. Ther. 2018 26 1840 1854 10.1016/j.ymthe.2018.04.018 29759938 PMC6035736 · DOI
  24. [26]Gailhouste L. Liew L.C. Yasukawa K. Hagiwara K. Iwazaki N. Yamada Y. Hatada I. Ochiya T. Epigenetic Reprogramming of Human Hepatoma Cells: A Low-Cost Option for Drug Metabolism Assessment Cell Mol. Gastroenterol. Hepatol. 2017 5 454 457 10.1016/j.jcmgh.2017.11.006 29675460 PMC5904034 · DOI
  25. [27]Dannenberg L.O. Edenberg H.J. Epigenetics of Gene Expression in Human Hepatoma Cells: Expression Profiling the Response to Inhibition of DNA Methylation and Histone Deacetylation BMC Genom. 2006 7 181 10.1186/1471-2164-7-181 PMC1574318 16854234 · DOI
  26. [29]Hsiao L.-L. Dangond F. Yoshida T. Hong R. Jensen R.V. Misra J. Dillon W. Lee K.F. Clark K.E. Haverty P. A Compendium of Gene Expression in Normal Human Tissues Physiol. Genom. 2001 7 97 104 10.1152/physiolgenomics.00040.2001 11773596 · DOI
  27. [30]Morgan H.D. Santos F. Green K. Dean W. Reik W. Epigenetic Reprogramming in Mammals Hum. Mol. Genet 2005 14 R47 R58 10.1093/hmg/ddi114 15809273 · DOI
  28. [32]Eden A. Gaudet F. Waghmare A. Jaenisch R. Chromosomal Instability and Tumors Promoted by DNA Hypomethylation Science 2003 300 455 10.1126/science.1083557 12702868 · DOI
  29. [33]Hernandez-Meza G. Felden J. Gonzalez-Kozlova E.E. Garcia-Lezana T. Peix J. Portela A. Craig A.J. Sayols S. Schwartz M. Losic B. DNA Methylation Profiling of Human Hepatocarcinogenesis Hepatology 2021 74 183 199 10.1002/hep.31659 33237575 PMC8144238 · DOI
  30. [34]Iyer M.K. Niknafs Y.S. Malik R. Singhal U. Sahu A. Hosono Y. Barrette T.R. Prensner J.R. Evans J.R. Zhao S. The Landscape of Long Noncoding RNAs in the Human Transcriptome Nat. Genet. 2015 47 199 208 10.1038/ng.3192 25599403 PMC4417758 · DOI · Paper page
  31. [35]Mai H. Zhou B. Liu L. Yang F. Conran C. Ji Y. Hou J. Jiang D. Molecular Pattern of LncRNAs in Hepatocellular Carcinoma J. Exp. Clin. Cancer Res. Cr. 2019 38 198 10.1186/s13046-019-1213-0 31097003 PMC6524221 · DOI
  32. [36]Aran D. Camarda R. Odegaard J. Paik H. Oskotsky B. Krings G. Goga A. Sirota M. Butte A.J. Comprehensive Analysis of Normal Adjacent to Tumor Transcriptomes Nat. Commun. 2017 8 1077 10.1038/s41467-017-01027-z 29057876 PMC5651823 · DOI
  33. [37]Esposti D.D. Hernandez-Vargas H. Voegele C. Fernandez-Jimenez N. Forey N. Bancel B. Calvez-Kelm F.L. McKay J. Merle P. Herceg Z. Identification of Novel Long Non-Coding RNAs Deregulated in Hepatocellular Carcinoma Using RNA-Sequencing Oncotarget 2016 7 31862 31877 10.18632/oncotarget.7364 26887054 PMC5077982 · DOI
  34. [38]Li G. Shi H. Wang X. Wang B. Qu Q. Geng H. Sun H. Identification of Diagnostic Long Non-Coding RNA Biomarkers in Patients with Hepatocellular Carcinoma Mol. Med. Rep. 2019 20 1121 1130 10.3892/mmr.2019.10307 31173205 PMC6625424 · DOI
  35. [39]He J. Zuo Q. Hu B. Jin H. Wang C. Cheng Z. Deng X. Yang C. Ruan H. Yu C. A Novel, Liver-Specific Long Noncoding RNA LINC01093 Suppresses HCC Progression by Interaction with IGF2BP1 to Facilitate Decay of GLI1 MRNA Cancer Lett. 2019 450 98 109 10.1016/j.canlet.2019.02.033 30790682 · DOI
  36. [40]Burenina O.Y. Lazarevich N.L. Kustova I.F. Shavochkina D.A. Moroz E.A. Kudashkin N.E. Patyutko Y.I. Metelin A.V. Kim E.F. Skvortsov D.A. Panel of Potential LncRNA Biomarkers Can Distinguish Various Types of Liver Malignant and Benign Tumors J. Cancer Res. Clin. 2021 147 49 59 10.1007/s00432-020-03378-5 PMC11802012 32918630 · DOI
  37. [41]Zhao B. Ke K. Wang Y. Wang F. Shi Y. Zheng X. Yang X. Liu X. Liu J. HIF-1α and HDAC1 Mediated Regulation of FAM99A-MiR92a Signaling Contributes to Hypoxia Induced HCC Metastasis Signal. Transduct. Target Ther. 2020 5 118 10.1038/s41392-020-00223-6 32636357 PMC7341733 · DOI
  38. [42]Mo M. Liu S. Ma X. Tan C. Wei L. Sheng Y. Song Y. Zeng X. Huang D. Qiu X. A Liver-Specific LncRNA, FAM99B, Suppresses Hepatocellular Carcinoma Progression through Inhibition of Cell Proliferation, Migration, and Invasion J. Cancer Res. Clin. 2019 145 2027 2038 10.1007/s00432-019-02954-8 31243545 PMC11810180 · DOI
  39. [43]Jing G. Zheng X. Ji X. LncRNA HAND2-AS1 Overexpression Inhibits Cancer Cell Proliferation in Hepatocellular Carcinoma by Downregulating RUNX2 Expression J. Clin. Lab Anal. 2021 35 e23717 10.1002/jcla.23717 33566427 PMC8059724 · DOI
  40. [44]Bi H.-Q. Li Z.-H. Zhang H. Long Noncoding RNA HAND2-AS1 Reduced the Viability of Hepatocellular Carcinoma via Targeting MicroRNA-300/SOCS5 Axis Hepatob. Pancreat. Dis. 2020 19 567 574 10.1016/j.hbpd.2020.02.011 32224127 · DOI
  41. [45]Lin B. He H. Zhang Q. Zhang J. Xu L. Zhou L. Zheng S. Wu L. Long Non-Coding RNA00844 Inhibits MAPK Signaling to Suppress the Progression of Hepatocellular Carcinoma by Targeting AZGP1 Ann. Transl. Med. 2020 8 1365 10.21037/atm-20-3848 33313110 PMC7723597 · DOI
  42. [46]Zhou W. Huang K. Zhang Q. Ye S. Zhong Z. Zeng C. Peng G. Li L. Ye Q. LINC00844 Promotes Proliferation and Migration of Hepatocellular Carcinoma by Regulating NDRG1 Expression PeerJ 2020 8 e8394 10.7717/peerj.8394 32025371 PMC6993750 · DOI
  43. [47]Ying J.F. Zhang Y.N. Song S.S. Hu Z.M. He X.L. Pan H.Y. Zhang C.W. Wang H.J. Li W.F. Mou X.Z. Decreased Expression of GBA3 Correlates with a Poor Prognosis in Hepatocellular Carcinoma Patients Neoplasma 2020 67 1139 1145 10.4149/neo_2020_190928N980 32412773 · DOI
  44. [48]Gu X. Zheng Q. Chu Q. Zhu H. HAND2-AS1: A Functional Cancer-Related Long Non-Coding RNA Biomed. Pharm. 2021 137 111317 10.1016/j.biopha.2021.111317 33556872 · DOI
  45. [49]Zhu Y. Zhang X. Wang L. Zhu X. Xia Z. Xu L. Xu J. FENDRR Suppresses Cervical Cancer Proliferation and Invasion by Targeting MiR-15a/b-5p and Regulating TUBA1A Expression Cancer Cell Int. 2020 20 152 10.1186/s12935-020-01223-w 32398968 PMC7204253 · DOI
  46. [50]Zhang M.-Y. Zhang Z.-L. Cui H.-X. Wang R.-K. Fu L. Long Non-Coding RNA FENDRR Inhibits NSCLC Cell Growth and Aggressiveness by Sponging MiR Eur. Rev. Med. Pharmacol. Sci. 2018 22 8324 8332 10.26355/eurrev_201812_16530 30556873 · DOI
  47. [51]Liu L. Yue H. Liu Q. Yuan J. Li J. Wei G. Chen X. Lu Y. Guo M. Luo J. LncRNA MT1JP Functions as a Tumor Suppressor by Interacting with TIAR to Modulate the P53 Pathway Oncotarget 2016 7 15787 15800 10.18632/oncotarget.7487 26909858 PMC4941277 · DOI
  48. [52]Wu H. Li S. Long Non-Coding RNA MT1JP Exerts Anti-Cancer Effects in Breast Cancer Cells by Regulating MiR-92-3p Gen. Physiol. Biophys. 2020 39 59 67 10.4149/gpb_2019039 32039825 · DOI
  49. [53]Baylin S.B. Esteller M. Rountree M.R. Bachman K.E. Schuebel K. Herman J.G. Aberrant Patterns of DNA Methylation, Chromatin Formation and Gene Expression in Cancer Hum. Mol. Genet. 2001 10 687 692 10.1093/hmg/10.7.687 11257100 · DOI
  50. [54]Sun M. Lv S. Zhong J. Identification of LncRNA FAM99A Gene as a Prognostic Biomarker of Hepatocellular Carcinoma Research Square Durham, NC, USA 2020 10.21203/rs.3.rs-16068/v1 · DOI
  51. [55]Hanahan D. Hallmarks of Cancer: New Dimensions Cancer Discov. 2022 12 31 46 10.1158/2159-8290.CD-21-1059 35022204 · DOI · Paper page
  52. [56]Quinn J.J. Chang H.Y. Unique Features of Long Non-Coding RNA Biogenesis and Function Nat. Rev. Genet. 2016 17 47 62 10.1038/nrg.2015.10 26666209 · DOI
  53. [57]Guo T. Wang H. Liu P. Xiao Y. Wu P. Wang Y. Chen B. Zhao Q. Liu Z. Liu Q. SNHG6 Acts as a Genome-Wide Hypomethylation Trigger via Coupling of MiR-1297-Mediated S-Adenosylmethionine-Dependent Positive Feedback Loops Cancer Res. 2018 78 3849 3864 10.1158/0008-5472.CAN-17-3833 29844127 · DOI

Authors
Recalde, M., Gárate-Rascón, M., Herranz, J. M., Elizalde, M., Azkona, M., Unfried, J. P., Boix, L., Reig, M., Sangro, B., Fernández-Barrena, M. G., Fortes, P., Ávila, M. A., Berasain, C., & Arechederra, M.
Affiliations
  • Centro de Investigación Médica Aplicada (ES)
  • Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
  • Instituto de Salud Carlos III (ES)
Corresponding author
  • Berasain, Carmen
  • Arechederra, María
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2022-04-19
Volume
14
Issue
9
Pages
2048
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers14092048
PMC
PMC9102946
OpenAlex
W4224282213
Cited by
14
References
57
Citations by year
2026: 2 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 1
FWCI
1.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Instituto de Salud Carlos III (PI19/00163, PI19/00742)
  • Gobierno de Navarra (55/2018)
  • Ministerio de Ciencia, Innovación y Universidades (PID2019‐104265RBI00/AEI/10.13039/501100011033, PID2019-104878RB-100AEI/10.13039/501100011033, UE/RTI2018-101759-B-I00, BES-2017-079883, FPU18/01461, RYC2018-024475-1)
  • Fundación Científica Asociación Española Contra el Cáncer (POSTD18014AREC)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords
long non-coding RNA, DNA methylation, hepatocellular carcinoma, hepatocarcinogenesis, promoter hypermethylation, hepatic differentiation, tumor grade, prognosis, HepaRG cells, liver-specific gene expression

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