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Dichotomous Effects of Glypican-4 on Cancer Progression and Its Crosstalk with Oncogenes. Int. J. Mol. Sci. 2024, 25, 3945. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms25073945  \nAcademic Editor: Nobuaki Higashi  \nReceived: 19 February 2024  \nRevised: 25 March 2024  \nAccepted: 29 March 2024  \nPublished: 2 April 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Experimental Medical Science, Glycobiology Group, Lund University, Biomedical Center A13, SE-221 84 Lund, Sweden; [vi8354ch-s@student.lu.se](vi8354ch-s@student.lu.se) (V.C.H.); [fang.cheng@med.lu.se](fang.cheng@med.lu.se) (F.C.)  \n2 Genevia Technologies Oy, 33100 Tampere, Finland; [grigorios.georgolopoulos@geneviatechnologies.com](grigorios.georgolopoulos@geneviatechnologies.com)  \n* Correspondence: [katrin.mani@med.lu.se](katrin.mani@med.lu.se)  \nAbstract: Glypicans are linked to various aspects of neoplastic behavior, and their therapeutic value has been proposed in different cancers. Here, we have systematically assessed the impact of GPC4 on cancer progression through functional genomics and transcriptomic analyses across a broad range of cancers. Survival analysis using TCGA cancer patient data reveals divergent effects of GPC4 expression across various cancer types, revealing elevated GPC4 expression levels to be associated with both poor and favorable prognoses in a cancer-dependent manner. Detailed investigation of the role of GPC4 in glioblastoma and non-small cell lung adenocarcinoma by genetic perturbation studies displays opposing effects on these cancers, where the knockout of GPC4 with CRISPR/Cas9 attenuated proliferation of glioblastoma and augmented proliferation of lung adenocarcinoma cells and the overexpression of GPC4 exhibited a significant and opposite effect. Further, the overexpression of GPC4 in GPC4-knocked-down glioblastoma cells restored the proliferation, indicating its mitogenic effect in this cancer type. Additionally, a survival analysis of TCGA patient data substantiated these findings, revealing an association between elevated levels of GPC4 and a poor prognosis in glioblastoma, while indicating a favorable outcome in lung carcinoma patients. Finally, through transcriptomic analysis, we attempted to assign mechanisms of action to GPC4, as we find it implicated in cell cycle control and survival core pathways. The analysis revealed upregulation of oncogenes, including FGF5, TGF-β superfamily members, and ITGA-5 in glioblastoma, which were downregulated in lung adenocarcinoma patients. Our findings illuminate the pleiotropic effect of GPC4 in cancer, underscoring its potential as a putative prognostic biomarker and indicating its therapeutic implications in a cancer type dependent manner.  \nKeywords: glypican 4; TCGA; non-small cell lung carcinoma; glioblastoma; CRISPR/Cas9  \n1. Introduction  \nComprehending molecular alterations in cancer is crucial for identifying novel biomarkers and diagnosis tools and to find new therapeutic targets. Tumor microenvironments, including dividing cancer cells, stroma cells, infiltrating inflammatory cells, tumor vascular networks, and a myriad of signaling molecules and extra cellular matrix components secreted by both the tumor and stroma cells, play pivotal roles in cancer development. Among various factors contributing to this complex network, increasing evidence highlig","cbCaia9t3V6Yu3O4","https://ap.wps.com/l/cbCaia9t3V6Yu3O4","pdf",6723801,22,"English","# Abstract\n# Keywords\n# Introduction","[{\"question\":\"What evidence is used to assess the impact of GPC4 on cancer progression?\",\"answer\":\"The study combines functional genomics and transcriptomic analyses across many cancer types, supported by survival analysis using TCGA patient data and targeted genetic perturbation experiments.\"},{\"question\":\"How do GPC4 expression and manipulation affect glioblastoma versus lung adenocarcinoma?\",\"answer\":\"GPC4 knockout via CRISPR/Cas9 attenuates proliferation of glioblastoma cells while augmenting proliferation in lung adenocarcinoma cells; overexpression produces the opposite effects. Restoring GPC4 in knocked-down glioblastoma cells rescues proliferation.\"},{\"question\":\"What molecular mechanisms are proposed for GPC4 activity?\",\"answer\":\"Transcriptomic analyses suggest GPC4 involvement in cell-cycle control and survival core pathways, with oncogene upregulation such as FGF5, TGF-β superfamily members, and ITGA-5 in glioblastoma and downregulation in lung adenocarcinoma.\"}]","Dichotomous Effects of Glypican-4 on Cancer Progression and Its Crosstalk with Oncogenes | PDF",1790001831,55]