{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T12:28:47Z","timestamp":1775737727078,"version":"3.50.1"},"reference-count":37,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T00:00:00Z","timestamp":1573516800000},"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>Sema3C protein, a member of the class 3 family of secreted semaphorins, play an important role in tumor development by regulating cell proliferation, migration, invasion, and angiogenesis processes. Depending on the type and malignancy grade of the tumor, Sema3C function remains controversial. In this study, we constructed a stably overexpressing Sema3C glioblastoma cell line U87 MG and tested it on the chicken embryo chorioallantoic membrane (CAM) model with the aim to reveal Sema3C protein function on angiogenesis process in ovo. Our experiments showed that Sema3C not only affects angiogenesis of CAM by inhibiting neovascularization but also acts as an anti-tumorigenic molecule by hampering U87 MG cell invasion into mesenchyme. The effects of Sema3C on CAM were similar to the effects of anti-epileptic drug sodium valproate (NaVP). Both, anti-angiogenic and anti-tumorigenic activities of Sema3C were enhanced by the treatment of NaVP and, importantly, were not attributed to the cytotoxic effects. Our studies suggest that Sema3C could be a promising target for glioblastoma treatment.<\/jats:p>","DOI":"10.3390\/ijms20225672","type":"journal-article","created":{"date-parts":[[2019,11,13]],"date-time":"2019-11-13T09:11:27Z","timestamp":1573636287000},"page":"5672","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["The Anti-Tumorigenic Activity of Sema3C in the Chick Embryo Chorioallantoic Membrane Model"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0837-5846","authenticated-orcid":false,"given":"Indr\u0117","family":"Valiulyt\u0117","sequence":"first","affiliation":[{"name":"Neuroscience Institute, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R\u016bta","family":"Curk\u016bnavi\u010di\u016bt\u0117","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Ribokait\u0117","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arunas","family":"Kazlauskas","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Vaitkevi\u010di\u016bt\u0117","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K\u0119stutis","family":"Skauminas","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3611-2509","authenticated-orcid":false,"given":"Angelija","family":"Valan\u010di\u016bt\u0117","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/gb-2006-7-3-211","article-title":"The Semaphorins","volume":"7","author":"Yazdani","year":"2006","journal-title":"Genome Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-4939-6448-2_1","article-title":"Semaphorins and Their Signaling Mechanisms","volume":"1493","author":"Alto","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1080\/19336918.2016.1197478","article-title":"The Role of the Semaphorins in Cancer","volume":"10","author":"Neufeld","year":"2016","journal-title":"Cell Adh. Migr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"556","DOI":"10.3390\/ijms20030556","article-title":"Class-3 Semaphorins and Their Receptors: Potent Multifunctional Modulators of Tumor Progression","volume":"20","author":"Toledano","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"ref_5","first-page":"1663","article-title":"The Emerging Role of Class-3 Semaphorins and Their Neuropilin Receptors in Oncology","volume":"7","author":"Nasarre","year":"2014","journal-title":"Onco. Targets. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hui, D.H.F., Tam, K.J., Jiao, I.Z.F., and Ong, C.J. (2019). Semaphorin 3C as a Therapeutic Target in Prostate and Other Cancers. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030774"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Hao, J., and Yu, J.S. (2018). Semaphorin 3C and Its Receptors in Cancer and Cancer Stem-Like Cells. Biomedicines, 6.","DOI":"10.3390\/biomedicines6020042"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.15252\/emmm.201404922","article-title":"Semaphorin-3C Signals through Neuropilin-1 and PlexinD1 Receptors to Inhibit Pathological Angiogenesis","volume":"7","author":"Yang","year":"2015","journal-title":"EMBO Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1158\/0008-5472.CAN-14-2464","article-title":"Full-Length Semaphorin-3C Is an Inhibitor of Tumor Lymphangiogenesis and Metastasis","volume":"75","author":"Mumblat","year":"2015","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Toledano, S., Lu, H., Palacio, A., Ziv, K., Kessler, O., Schaal, S., Neufeld, G., and Barak, Y. (2016). A Sema3C Mutant Resistant to Cleavage by Furin (FR-Sema3C) Inhibits Choroidal Neovascularization. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168122"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1590\/1414-431x20187786","article-title":"Importance of the Putative Furin Recognition Site 742RNRR745 for Antiangiogenic Sema3C Activity in Vitro","volume":"51","author":"Valiulyte","year":"2018","journal-title":"Brazilian J. Med. Biol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s13000-015-0298-9","article-title":"High Level of Sema3C Is Associated with Glioma Malignancy","volume":"10","author":"Steponaitis","year":"2015","journal-title":"Diagn. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1111\/cas.12003","article-title":"Semaphorin 3C Is Involved in the Progression of Gastric Cancer","volume":"103","author":"Miyato","year":"2012","journal-title":"Cancer Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1016\/j.celrep.2014.10.055","article-title":"Sema3C Promotes the Survival and Tumorigenicity of Glioma Stem Cells through Rac1 Activation","volume":"9","author":"Man","year":"2014","journal-title":"Cell Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2010\/351908","article-title":"Molecular Therapeutic Targets for Glioma Angiogenesis","volume":"2010","author":"Takano","year":"2010","journal-title":"J. Oncol."},{"key":"ref_16","first-page":"6326053","article-title":"The Effect of Sodium Valproate on the Glioblastoma U87 Cell Line Tumor Development on the Chicken Embryo Chorioallantoic Membrane and on EZH2 and P53 Expression","volume":"2017","author":"Kazlauskas","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.clineuro.2018.09.019","article-title":"The Survival Effect of Valproic Acid in Glioblastoma and Its Current Trend: A Systematic Review and Meta-Analysis","volume":"174","author":"Lu","year":"2018","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejphar.2014.07.025","article-title":"Cisplatin in Cancer Therapy: Molecular Mechanisms of Action","volume":"740","author":"Shaloam","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1111\/j.1365-2710.2005.00671.x","article-title":"Valproate: A Simple Chemical with so Much to Offer","volume":"30","author":"Mba","year":"2005","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1684\/j.1950-6945.2004.tb00053.x","article-title":"Antiepileptic Drugs: Indications Other than Epilepsy","volume":"6","author":"Spina","year":"2004","journal-title":"Epileptic. Disord."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1002\/med.20027","article-title":"Evolving Anticancer Drug Valproic Acid: Insights into the Mechanism and Clinical Studies","volume":"25","author":"Blaheta","year":"2005","journal-title":"Med. Res. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4172\/2155-9929.1000240","article-title":"The Role of Histone Deacetylase (HDAC) as a Biomarker in Cancer","volume":"6","author":"Moradzadeh","year":"2015","journal-title":"J. Mol. Biomark. Diagn."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"a018713","DOI":"10.1101\/cshperspect.a018713","article-title":"Erasers of Histone Acetylation: The Histone Deacetylase Enzymes","volume":"6","author":"Seto","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"18577","DOI":"10.18632\/oncotarget.14612","article-title":"Advances in Epigenetic Glioblastoma Therapy","volume":"8","author":"Lee","year":"2017","journal-title":"Oncotarget"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"36734","DOI":"10.1074\/jbc.M101287200","article-title":"Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen*","volume":"276","author":"Phiel","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s11060-007-9402-7","article-title":"Valproic Acid Induces P21 and Topoisomerase-II (\u03b1\/\u03b2) Expression and Synergistically Enhances Etoposide Cytotoxicity in Human Glioblastoma Cell Lines","volume":"85","author":"Das","year":"2007","journal-title":"J. Neurooncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"35004","DOI":"10.18632\/oncotarget.5253","article-title":"Valproic Acid Enhances the Efficacy of Radiation Therapy by Protecting Normal Hippocampal Neurons and Sensitizing Malignant Glioblastoma Cells","volume":"6","author":"Thotala","year":"2015","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14666","DOI":"10.18632\/oncotarget.14716","article-title":"Valproic Acid Inhibits Glioblastoma Multiforme Cell Growth via Paraoxonase 2 Expression","volume":"8","author":"Tseng","year":"2017","journal-title":"Oncotarget"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"186","DOI":"10.2176\/nmc.52.186","article-title":"Valproic Acid Inhibits Angiogenesis In Vitro and Glioma Angiogenesis In Vivo in the Brain","volume":"52","author":"Osuka","year":"2012","journal-title":"Neurol. Med. Chir."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s11060-016-2056-6","article-title":"The Effects of Antiepileptic Drugs on the Growth of Glioblastoma Cell Lines","volume":"127","author":"Lee","year":"2016","journal-title":"J. Neurooncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6816","DOI":"10.1007\/s12035-018-0895-1","article-title":"Combination Therapy with Sulfasalazine and Valproic Acid Promotes Human Glioblastoma Cell Death Through Imbalance of the Intracellular Oxidative Response","volume":"55","author":"Garcia","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"11501","DOI":"10.1038\/s41598-017-11914-6","article-title":"Semaphorin 3 C Drives Epithelial-to-Mesenchymal Transition, Invasiveness, and Stem-like Characteristics in Prostate Cells","volume":"7","author":"Tam","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"172551","DOI":"10.1016\/j.ejphar.2019.172551","article-title":"Up-Regulation of TIF1\u03b3 by Valproic Acid Inhibits the Epithelial Mesenchymal Transition in Prostate Carcinoma through TGF-\u03b2\/Smad Signaling Pathway","volume":"860","author":"Qi","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1038\/sj.bjc.6604641","article-title":"Semaphorin, Neuropilin and VEGF Expression in Glial Tumours: SEMA3G, a Prognostic Marker?","volume":"99","author":"Wager","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"219","DOI":"10.15252\/emmm.201707689","article-title":"SEMA3C Drives Cancer Growth by Transactivating Multiple Receptor Tyrosine Kinases via Plexin B1","volume":"10","author":"Peacock","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.canlet.2017.03.014","article-title":"Increased semaphorin 3c expression promotes tumor growth and metastasis in pancreatic ductal adenocarcinoma by activating the ERK1\/2 signaling pathway","volume":"397","author":"Xu","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji\u2014An Open Platform for Biological Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/22\/5672\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:33:57Z","timestamp":1760189637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/22\/5672"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,12]]},"references-count":37,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["ijms20225672"],"URL":"https:\/\/doi.org\/10.3390\/ijms20225672","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,12]]}}}