{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T04:13:48Z","timestamp":1777176828714,"version":"3.51.4"},"reference-count":51,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T00:00:00Z","timestamp":1636070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["GA KK01.1.1.01.0007"],"award-info":[{"award-number":["GA KK01.1.1.01.0007"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In the search for molecular candidates for targeted meningioma therapies, increasing attention has been paid to the role of signaling pathways in the development and progression of intracranial meningiomas. Although it is well known that the Wnt signaling pathway is involved in meningioma progression, the role of its central mediator, DVL1, is still unclear. In order to investigate the influence of DVL1 gene alterations on the progression of human intracranial meningioma, we focused on its central PDZ domain, which is responsible for DVL interaction with the Fzd receptor and the phosphorylation of DVL mediated through the casein kinases CK1 and CK2. A genetic analysis of genomic instability revealed the existence of microsatellite instability in 9.09% and the loss of heterozygosity in 6.06% of the samples. The sequencing of the PDZ gene region showed repetitive deletions of two bases located in intron 7 and exon 8, and a duplication in intron 8 in most samples, with different outcomes on the biological function of the DVL1 protein. Immunohistochemistry revealed that the nuclear expression of DVL1 was significantly correlated with a higher expression of active \u03b2-catenin (p = 0.029) and a higher meningioma grade (p = 0.030), which leads to the conclusion that it could be used as biomarker for meningioma progression and the activation of the Wnt signaling pathway.<\/jats:p>","DOI":"10.3390\/ijms222111996","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T10:33:09Z","timestamp":1636108389000},"page":"11996","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Decoding the Role of DVL1 in Intracranial Meningioma"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6587-8314","authenticated-orcid":false,"given":"Anja","family":"Bukovac","sequence":"first","affiliation":[{"name":"Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0214-9189","authenticated-orcid":false,"given":"Katarina","family":"Dragi\u010devi\u0107","sequence":"additional","affiliation":[{"name":"Biotech Research & Innovation Centre, University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Kafka","sequence":"additional","affiliation":[{"name":"Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3018-5248","authenticated-orcid":false,"given":"Darko","family":"Ore\u0161kovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University Hospital Dubrava, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanja","family":"Cesarec-Augustinovi\u0107","sequence":"additional","affiliation":[{"name":"\u201cLjudevit Jurak\u201d Department of Pathology and Cytology, Clinical Hospital Center \u201cSestre milosrdnice\u201d, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3334-7671","authenticated-orcid":false,"given":"Nives","family":"Pe\u0107ina-\u0160laus","sequence":"additional","affiliation":[{"name":"Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,5]]},"reference":[{"key":"ref_1","unstructured":"(2021, January 30). The Central Brain Tumor Registry of the United States (CBTRUS). Available online: https:\/\/cbtrus.org\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"v1","DOI":"10.1093\/neuonc\/noz150","article-title":"CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2012\u20132016","volume":"21","author":"Ostrom","year":"2019","journal-title":"Neuro-Oncology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1097\/NEN.0b013e31826bf704","article-title":"Genetic alterations associated with progression and recurrence in meningiomas","volume":"71","author":"Mur","year":"2012","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Pe\u0107ina-\u0160laus, N., Kafka, A., and Lechpammer, M. (2016). Molecular genetics of intracranial meningiomas with emphasis on canonical Wnt signalling. Cancers, 8.","DOI":"10.3390\/cancers8070067"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.clineuro.2017.05.002","article-title":"Genetic and epigenetic alterations in meningiomas","volume":"158","author":"Galani","year":"2017","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s10571-017-0498-9","article-title":"Exploration of involved key genes and signaling diversity in brain tumors","volume":"38","author":"Nasser","year":"2017","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nrneurol.2017.168","article-title":"Advances in meningioma genetics: Novel therapeutic opportunities","volume":"14","author":"Preusser","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1055\/s-0038-1636502","article-title":"Meningiomas: Overview and new directions in therapy","volume":"38","author":"Wang","year":"2018","journal-title":"Semin. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.clineuro.2018.12.004","article-title":"Molecular alterations in meningiomas: Literature review","volume":"176","author":"Pereira","year":"2019","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Vall\u00e9e, A., LeCarpentier, Y., and Vall\u00e9e, J.-N. (2019). Targeting the canonical WNT\/\u03b2-catenin pathway in cancer treatment using non-steroidal anti-inflammatory drugs. Cells, 8.","DOI":"10.3390\/cells8070726"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/nrd4233","article-title":"Can we safely target the WNT pathway?","volume":"13","author":"Kahn","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1177\/1073858416667270","article-title":"How Wnt signaling builds the brain: Bridging development and disease","volume":"23","author":"Noelanders","year":"2016","journal-title":"Neuroscientist"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.1097\/MD.0000000000004765","article-title":"Cancer stem cell signaling pathways","volume":"95","author":"Matsui","year":"2016","journal-title":"Medicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/bs.pmbts.2017.11.018","article-title":"Wnt signaling in the central nervous system: New insights in health and disease","volume":"153","author":"Oliva","year":"2018","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"El-Sahli, S., Xie, Y., Wang, L., and Liu, S. (2019). Wnt signaling in cancer metabolism and immunity. Cancers, 11.","DOI":"10.3390\/cancers11070904"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"826","DOI":"10.3390\/cells8080826","article-title":"WNT signaling in disease","volume":"8","author":"Ng","year":"2019","journal-title":"Cells"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"E7","DOI":"10.3171\/2011.2.FOCUS1117","article-title":"Molecular genetics of meningiomas: A systematic review of the current literature and potential basis for future treatment paradigms","volume":"30","author":"Pham","year":"2011","journal-title":"Neurosurg. Focus"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.3390\/cancers13071633","article-title":"Are we benign? What can Wnt signaling pathway and epithelial to mesenchymal transition tell us about intracranial meningioma progression","volume":"13","author":"Bukovac","year":"2021","journal-title":"Cancers"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3325\/cmj.2014.55.459","article-title":"The cellular story of dishevelleds","volume":"55","author":"Kafka","year":"2014","journal-title":"Croat. Med. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e00142","DOI":"10.1042\/BSR20140119","article-title":"Updating the Wnt pathways","volume":"34","author":"Yu","year":"2014","journal-title":"Biosci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"165902","DOI":"10.1242\/dev.165902","article-title":"Wnt signalling: Conquering complexity","volume":"145","author":"Wiese","year":"2018","journal-title":"Development"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1146\/annurev-cancerbio-030419-033628","article-title":"WNT and \u03b2-catenin in cancer: Genes and therapy","volume":"4","author":"Jackstadt","year":"2020","journal-title":"Annu. Rev. Cancer Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cellsig.2018.03.004","article-title":"Dishevelled: A masterful conductor of complex Wnt signals","volume":"47","author":"Sharma","year":"2018","journal-title":"Cell. Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1111\/j.1349-7006.2003.tb01475.x","article-title":"Amplification, up-regulation and over-expression of DVL-1, the human counterpart of the Drosophila disheveled gene, in primary breast cancers","volume":"94","author":"Nagahata","year":"2003","journal-title":"Cancer Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1111\/jcmm.13969","article-title":"Different behaviour of DVL1, DVL2, DVL3 in astrocytoma malignancy grades and their association to TCF1 and LEF1 upregulation","volume":"23","author":"Kafka","year":"2018","journal-title":"J. Cell. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1093\/hmg\/9.2.237","article-title":"Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1","volume":"9","author":"Ars","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"10505","DOI":"10.1128\/MCB.24.24.10505-10514.2004","article-title":"Influence of RNA secondary structure on the pre-mRNA splicing process","volume":"24","author":"Buratti","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Rogic, S., Montpetit, B., Hoos, H., Mackworth, A., Ouellette, B., and Hieter, P. (2008). Correlation between the secondary structure of pre-mRNA introns and the efficiency of splicing in Saccharomyces cerevisiae. BMC Genom., 9.","DOI":"10.1186\/1471-2164-9-355"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1134\/S0026893316060170","article-title":"Role of pre-mRNA secondary structures in the regulation of alternative splicing","volume":"50","author":"Rubtsov","year":"2016","journal-title":"Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1080\/15476286.2016.1208893","article-title":"RNA structure in splicing: An evolutionary perspective","volume":"13","author":"Lin","year":"2016","journal-title":"RNA Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4873","DOI":"10.1038\/sj.onc.1207642","article-title":"Truncated mutants of the putative Wnt receptor LRP6\/Arrow can stabilize \u03b2-catenin independently of Frizzled proteins","volume":"23","author":"Brennan","year":"2004","journal-title":"Oncogene"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/ijc.21826","article-title":"Truncated APC is required for cell proliferation and DNA replication","volume":"119","author":"Schneikert","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.jtbi.2010.03.046","article-title":"The rules of variation: Amino acid exchange according to the rotating circular genetic code","volume":"264","year":"2010","journal-title":"J. Theor. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"20492","DOI":"10.3390\/ijms141020492","article-title":"Significant overexpression of DVL1 in Taiwanese colorectal cancer patients with liver metastasis","volume":"14","author":"Huang","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.7314\/APJCP.2015.16.6.2385","article-title":"Expression of DDR1 and DVL1 in invasive ductal and lobular breast carcinoma does not correlate with histological type, grade and hormone receptor status","volume":"16","author":"Ameli","year":"2015","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"16257","DOI":"10.1038\/s41598-019-52723-3","article-title":"Acetylation of conserved DVL-1 lysines regulates its nuclear translocation and binding to gene promoters in triple-negative breast cancer","volume":"9","author":"Sharma","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/apm.13012","article-title":"Dishevelled family proteins in serous ovarian carcinomas: A clinicopathologic and molecular study","volume":"128","author":"Kardum","year":"2020","journal-title":"APMIS"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1177\/030089160509100616","article-title":"Upregulation and overexpression of DVL1, the human counterpart of the Drosophila dishevelled gene, in prostate cancer","volume":"91","author":"Mizutani","year":"2005","journal-title":"Tumori"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.lungcan.2008.06.018","article-title":"Dishevelled family proteins are expressed in non-small cell lung cancer and function differentially on tumor progression","volume":"62","author":"Wei","year":"2008","journal-title":"Lung Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1111\/cpr.12161","article-title":"Silencing dishevelled-1 sensitizes paclitaxel-resistant human ovarian cancer cells via AKT\/GSK-3\u03b2\/\u03b2-catenin signalling","volume":"48","author":"Zhang","year":"2015","journal-title":"Cell Prolif."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"10635","DOI":"10.3390\/ijms150610635","article-title":"Brain metastases from lung cancer show increased expression of DVL1, DVL3 and beta-catenin and down-regulation of E-cadherin","volume":"15","author":"Kafka","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO classification of tumors of the central nervous system: A summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro-Oncology"},{"key":"ref_43","unstructured":"Green, M.R., and Sambrook, J. (2012). Molecular Cloning\u2014A Laboratory Manual, Cold Spring Harbor Laboratory Press. [4th ed.]."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","article-title":"A simple salting out procedure for extracting DNA from human nucleated cells","volume":"16","author":"Miller","year":"1988","journal-title":"Nucleic Acids Res."},{"key":"ref_45","unstructured":"(2020, October 25). National Center for Biotechnology Information\u2014NCBI, Available online: https:\/\/www.ncbi.nlm.nih.gov."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ye, J., Coulouris, G., Zaretskaya, I., Cutcutache, I., Rozen, S., and Madden, T. (2012). Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC Bioinform., 13.","DOI":"10.1186\/1471-2105-13-134"},{"key":"ref_47","unstructured":"(2021, January 25). National Center for Biotechnology Information\u2014NCBI, Available online: https:\/\/www.ncbi.nlm.nih.gov\/nucleotide\/NG_008048?report=genbank&log$=nuclalign&blast_rank=1&RID=0."},{"key":"ref_48","unstructured":"(2021, January 30). Protein Variation Effect Analyzer\u2014PROVEAN. Available online: http:\/\/provean.jcvi.org\/index.php."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.lungcan.2013.07.016","article-title":"Evaluation of EGFR protein expression by immunohistochemistry using H-score and the magnification rule: Re-analysis of the SATURN study","volume":"82","author":"Brugger","year":"2013","journal-title":"Lung Cancer"},{"key":"ref_50","unstructured":"(2021, March 15). RStudio. Available online: https:\/\/rstudio.com\/."},{"key":"ref_51","unstructured":"(2021, March 15). CRAN. Available online: https:\/\/cran.r-project.org\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11996\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:26:27Z","timestamp":1760167587000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11996"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,5]]},"references-count":51,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222111996"],"URL":"https:\/\/doi.org\/10.3390\/ijms222111996","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,5]]}}}