{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T08:17:40Z","timestamp":1769761060227,"version":"3.49.0"},"reference-count":41,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,6,5]],"date-time":"2020-06-05T00:00:00Z","timestamp":1591315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Long non-coding RNAs (lncRNAs) are increasingly being identified as crucial regulators in pathologies like cancer. High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer (OC), one of the most lethal gynecological malignancies. LncRNAs, especially in cancers such as HGSC, could play a valuable role in diagnosis and even therapy. From RNA-sequencing analysis performed between an OC cell line, SKOV3, and a Fallopian Tube (FT) cell line, FT194, an important long non-coding RNA, HAND2 Anti sense RNA 1 (HAND2-AS1), was observed to be significantly downregulated in OCs when compared to FT. Its downregulation in HGSC was validated in different datasets and in a panel of HGSC cell lines. Furthermore, this study shows that the downregulation of HAND2-AS1 is caused by promoter hypermethylation in HGSC and behaves as a tumor suppressor in HGSC cell lines. Since therapeutic relevance is of key importance in HGSC research, for the first time, HAND2-AS1 upregulation was demonstrated to be one of the mechanisms through which HDAC inhibitor Panobinostat could be used in a strategy to increase HGSC cells\u2019 sensitivity to chemotherapeutic agents currently used in clinical trials. To unravel the mechanism by which HAND2-AS1 exerts its role, an in silico mRNA network was constructed using mRNAs whose expressions were positively and negatively correlated with this lncRNA in HGSC. Finally, a putative ceRNA network with possible miRNA targets of HAND2-AS1 and their mRNA targets was constructed, and the enriched Gene Ontology (GO) biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified.<\/jats:p>","DOI":"10.3390\/ijms21114059","type":"journal-article","created":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T05:16:14Z","timestamp":1591679774000},"page":"4059","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Long Non-Coding RNA HAND2-AS1 Acts as a Tumor Suppressor in High-Grade Serous Ovarian Carcinoma"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2813-330X","authenticated-orcid":false,"given":"Priyanka","family":"Gokulnath","sequence":"first","affiliation":[{"name":"IEOS\u2013Institute of Experimental Endocrinology and Oncology G. Salvatore, National Research Council, via S. Pansini 5, 80131 Napoli, Italy"},{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, 81100 Caserta, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0121-0002","authenticated-orcid":false,"given":"Tiziana","family":"de Cristofaro","sequence":"additional","affiliation":[{"name":"IEOS\u2013Institute of Experimental Endocrinology and Oncology G. Salvatore, National Research Council, via S. Pansini 5, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5348-8378","authenticated-orcid":false,"given":"Ichcha","family":"Manipur","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, 81100 Caserta, Italy"},{"name":"High Performance Computing and Networking Institute, National Research Council, via P. Castellino 111, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tina","family":"Di Palma","sequence":"additional","affiliation":[{"name":"IEOS\u2013Institute of Experimental Endocrinology and Oncology G. Salvatore, National Research Council, via S. Pansini 5, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3687-9737","authenticated-orcid":false,"given":"Amata Amy","family":"Soriano","sequence":"additional","affiliation":[{"name":"IEOS\u2013Institute of Experimental Endocrinology and Oncology G. Salvatore, National Research Council, via S. Pansini 5, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2870-8134","authenticated-orcid":false,"given":"Mario Rosario","family":"Guarracino","sequence":"additional","affiliation":[{"name":"High Performance Computing and Networking Institute, National Research Council, via P. Castellino 111, 80131 Napoli, Italy"},{"name":"HSE\u2013National Research University Higher School of Economics, LATNA Laboratory, 603155 Nizhny Novgorod, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5740-9769","authenticated-orcid":false,"given":"Mariastella","family":"Zannini","sequence":"additional","affiliation":[{"name":"IEOS\u2013Institute of Experimental Endocrinology and Oncology G. Salvatore, National Research Council, via S. Pansini 5, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Fernandes, J., Acu\u00f1a, S., Aoki, J., Floeter-Winter, L., and Muxel, S. (2019). Long Non-Coding RNAs in the Regulation of Gene Expression: Physiology and Disease. Non Coding RNA, 5.","DOI":"10.3390\/ncrna5010017"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Salviano-Silva, A., Lobo-Alves, S., Almeida, R., Malheiros, D., and Petzl-Erler, M. (2018). Besides Pathology: Long Non-Coding RNA in Cell and Tissue Homeostasis. Non Coding RNA, 4.","DOI":"10.3390\/ncrna4010003"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/nrc.2017.99","article-title":"Non-coding RNA networks in cancer","volume":"18","author":"Anastasiadou","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.ncrna.2018.03.001","article-title":"Exploring the mechanisms behind long noncoding RNAs and cancer","volume":"3","author":"Balas","year":"2018","journal-title":"Non Coding RNA Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1111\/his.13248","article-title":"High-grade serous carcinoma of tubo-ovarian origin: Recent developments","volume":"71","author":"Singh","year":"2017","journal-title":"Histopathology"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Testa, U., Petrucci, E., Pasquini, L., Castelli, G., and Pelosi, E. (2018). Ovarian Cancers: Genetic Abnormalities, Tumor Heterogeneity and Progression, Clonal Evolution and Cancer Stem Cells. Medicines, 5.","DOI":"10.3390\/medicines5010016"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1097\/GCO.0000000000000340","article-title":"Pathogenesis and heterogeneity of ovarian cancer","volume":"29","author":"Kroeger","year":"2017","journal-title":"Curr. Opin. Obstet. Gynecol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1016\/j.drudis.2018.04.010","article-title":"Role of lncRNAs in ovarian cancer: Defining new biomarkers for therapeutic purposes","volume":"23","author":"Tripathi","year":"2018","journal-title":"Drug Discov. Today"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/nature20128","article-title":"Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development","volume":"539","author":"Anderson","year":"2016","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3690","DOI":"10.1177\/0300060519849295","article-title":"Long non-coding RNA HAND2-AS1 downregulation predicts poor survival of patients with end-stage dilated cardiomyopathy","volume":"47","author":"Cheng","year":"2019","journal-title":"J. Int. Med. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Voth, H., Oberthuer, A., Simon, T., Kahlert, Y., Berthold, F., and Fischer, M. (2009). Co-regulated expression of HAND2 and DEIN by a bidirectional promoter with asymmetrical activity in neuroblastoma. BMC Mol. Biol., 10.","DOI":"10.1186\/1471-2199-10-28"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.canlet.2017.10.028","article-title":"Long non-coding RNA HAND2-AS1 inhibits invasion and metastasis in endometrioid endometrial carcinoma through inactivating neuromedin U","volume":"413","author":"Yang","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_13","first-page":"526","article-title":"Energy stress-induced lncRNA HAND2-AS1 represses HIF1\u03b1-mediated energy metabolism and inhibits osteosarcoma progression","volume":"8","author":"Kang","year":"2018","journal-title":"Am. J. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1016\/j.bbrc.2018.07.125","article-title":"LncRNA HAND2-AS1 sponging miR-1275 suppresses colorectal cancer progression by upregulating KLF14","volume":"503","author":"Zhou","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"BSR20181525","DOI":"10.1042\/BSR20181525","article-title":"LncRNA HAND2-AS1 inhibits non-small cell lung cancer migration, invasion and maintains cell stemness through the interactions with TGF-\u03b21","volume":"39","author":"Miao","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_16","first-page":"2103","article-title":"LncRNA HAND2-AS1 inhibits proliferation and promotes apoptosis of chronic myeloid leukemia cells by sponging with micRNA-1275","volume":"23","author":"Yang","year":"2019","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9564","DOI":"10.1002\/jcb.28233","article-title":"Long noncoding RNA HAND2-AS1 inhibits cancer cell proliferation, migration, and invasion in esophagus squamous cell carcinoma by regulating microRNA-21","volume":"120","author":"Yan","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chen, J., Lin, Y., Jia, Y., Xu, T., Wu, F., and Jin, Y. (2019). LncRNA HAND2-AS1 exerts anti-oncogenic effects on ovarian cancer via restoration of BCL2L11 as a sponge of microRNA-340-5p. J. Cell. Physiol.","DOI":"10.1002\/jcp.28911"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gokulnath, P., De Cristofaro, T., Manipur, I., Di Palma, T., Soriano, A.A., Guarracino, M.R., and Zannini, M. (2019). Long Non-Coding RNA MAGI2-AS3 is a New Player with a Tumor Suppressive Role in High Grade Serous Ovarian Carcinoma. Cancers, 11.","DOI":"10.3390\/cancers11122008"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Liu, P., Du, R., and Yu, X. (2019). LncRNA HAND2-AS1 overexpression inhibits cancer cell proliferation in melanoma by downregulating ROCK1. Oncol. Lett., 1\u20136.","DOI":"10.3892\/ol.2019.10402"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/path.4649","article-title":"In vitro and in vivo correlates of physiological and neoplastic human Fallopian tube stem cells","volume":"284","author":"Yamamoto","year":"2016","journal-title":"J. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"W98","DOI":"10.1093\/nar\/gkx247","article-title":"GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses","volume":"45","author":"Tang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1097\/IGC.0b013e31820e5cda","article-title":"Genome-wide de novo methylation in epithelial ovarian cancer","volume":"21","author":"Keshet","year":"2011","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D888","DOI":"10.1093\/nar\/gkw1123","article-title":"DiseaseMeth version 2.0: A major expansion and update of the human disease methylation database","volume":"45","author":"Xiong","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Hull, E.E., Montgomery, M.R., and Leyva, K.J. (2016). HDAC Inhibitors as Epigenetic Regulators of the Immune System: Impacts on Cancer Therapy and Inflammatory Diseases. Biomed Res. Int., 2016.","DOI":"10.1155\/2016\/8797206"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.tjog.2011.01.022","article-title":"Low-dose LBH589 increases the sensitivity of cisplatin to cisplatin-resistant ovarian cancer cells","volume":"50","author":"Ma","year":"2011","journal-title":"Taiwan J. Obstet. Gynecol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13048-016-0267-2","article-title":"Influence of a novel histone deacetylase inhibitor panobinostat (LBH589) on the growth of ovarian cancer","volume":"9","author":"Garrett","year":"2016","journal-title":"J. Ovarian Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Shi, K., Yin, X., Cai, M.C., Yan, Y., Jia, C., Ma, P., Zhang, S., Zhang, Z., Gu, Z., and Zhang, M. (2019). Pax8 regulon in human ovarian cancer links lineage dependency with epigenetic vulnerability to hdac inhibitors. Elife, 8.","DOI":"10.7554\/eLife.44306"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio Cancer Genomics Portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_30","first-page":"11","article-title":"Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal","volume":"6","author":"Gao","year":"2014","journal-title":"Sci Signal"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1093\/bioinformatics\/btt019","article-title":"CluePedia Cytoscape plugin: Pathway insights using integrated experimental and in silico data","volume":"29","author":"Bindea","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2515","DOI":"10.1093\/bioinformatics\/bty124","article-title":"GDCRNATools: An R\/Bioconductor package for integrative analysis of lncRNA, miRNA and mRNA data in GDC","volume":"34","author":"Li","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.jmig.2016.12.007","article-title":"Role of Fallopian Tubes in the Development of Ovarian Cancer","volume":"24","author":"Corzo","year":"2017","journal-title":"J. Minim. Invasive Gynecol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1002\/cncy.20089","article-title":"Utility of paired box gene 8 (PAX8) expression in fluid and fine-needle aspiration cytology: An immunohistochemical study of metastatic ovarian serous carcinoma","volume":"118","author":"McKnight","year":"2010","journal-title":"Cancer Cytopathol."},{"key":"ref_36","first-page":"1323","article-title":"Long non-coding RNA HAND2-AS1 targets glucose metabolism and inhibits cancer cell proliferation in osteosarcoma","volume":"18","author":"Chen","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_37","first-page":"1","article-title":"Jvenn: An interactive Venn diagram viewer","volume":"15","author":"Bardou","year":"2014","journal-title":"BMC Bioinf. Softw."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2-\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3242","DOI":"10.1016\/j.celrep.2017.03.015","article-title":"Phosphoproteomics of Primary Cells Reveals Druggable Kinase Signatures in Ovarian Cancer","volume":"18","author":"Francavilla","year":"2017","journal-title":"Cell Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"D231","DOI":"10.1093\/nar\/gkv1270","article-title":"DIANA-LncBase v2: Indexing microRNA targets on non-coding transcripts","volume":"44","author":"Paraskevopoulou","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"D296","DOI":"10.1093\/nar\/gkx1067","article-title":"MiRTarBase update 2018: A resource for experimentally validated microRNA-target interactions","volume":"46","author":"Chou","year":"2018","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/4059\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:36:07Z","timestamp":1760175367000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/4059"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,5]]},"references-count":41,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ijms21114059"],"URL":"https:\/\/doi.org\/10.3390\/ijms21114059","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,5]]}}}