{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T07:30:18Z","timestamp":1768721418489,"version":"3.49.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T00:00:00Z","timestamp":1654819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011789","name":"Department of Science and Technology of Jilin Province","doi-asserted-by":"publisher","award":["20200201510JC"],"award-info":[{"award-number":["20200201510JC"]}],"id":[{"id":"10.13039\/501100011789","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011789","name":"Department of Science and Technology of Jilin Province","doi-asserted-by":"publisher","award":["20210402021GH"],"award-info":[{"award-number":["20210402021GH"]}],"id":[{"id":"10.13039\/501100011789","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010211","name":"Education Department of Jilin Province","doi-asserted-by":"publisher","award":["JJKH20211147KJ"],"award-info":[{"award-number":["JJKH20211147KJ"]}],"id":[{"id":"10.13039\/501100010211","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Glioblastoma (GBM) is the most common primary brain malignant tumor, and patients with GBM have a poor prognosis. The tumor microenvironment (TME) is connected to tumorigenesis and prognosis. However, the TME-related genes and therapeutic targets in GBM are yet to be identified. Thus, the presented study aimed to identify TME-related biomarkers in GBM and develop a novel target for the treatment of the disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>ESTIMATE computational methods were utilized to estimate the amounts of stromal and immune components in 697 patients with glioma from the Cancer Genome Atlas database. Then, the protein\u2013protein interaction network and univariate Cox regression analyzed the differentially expressed genes. Serum amyloid A1 (SAA1) was determined to be a predictive factor. SAA1 expression was statistically significant in GBM compared to the normal samples and other glioma subtypes and negatively associated with survival. Independent prognostic analysis identified SAA1 as a TME-related prognostic factor. Furthermore, Western blot analysis showed that SAA1 is upregulated in GBM, which was confirmed by the external validation in the Chinese Glioma Genome Atlas. The gene set enrichment analysis in GBM revealed enrichment of immune-related activities in the SAA1 high-expression group, while mitosis and cell cycle were enriched in the low-expression group. CIBERSORT analysis of the tumor-infiltrating immune cell proportion revealed that M2 macrophages, neutrophils, activated mast cells, resting mast cells, and regulatory T cells were correlated with SAA1 expression. Finally, immune checkpoint genes, tumor mutation burden, and drug sensitivity were also analyzed between the high- and low-expression groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>SAA1 could be a distinctive gene between GBM and other subtype gliomas, and thus a novel biomarker for estimating the survival and TME status. The altered expression level shifts the primary function of SAA1 from cell cycle and mitosis to immune activity. High expression of SAA1 is associated with poor survival and upregulates the expression of LAIR1 and TNFSF14, thereby deeming it as the drug sensitivity indicator for XAV939, TGX-221, and lapatinib in GBM immune therapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2022.905561","type":"journal-article","created":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T05:16:58Z","timestamp":1654838218000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["SAA1 Expression as a Potential Prognostic Marker of the Tumor Microenvironment in Glioblastoma"],"prefix":"10.3389","volume":"13","author":[{"given":"Kangxi","family":"Cao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingyu","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baishun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaohui","family":"Ni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.canlet.2020.02.002","article-title":"Immunotherapy for glioma: current management and future application","volume":"476","author":"Xu","year":"2020","journal-title":"Cancer Lett."},{"key":"B2","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","article-title":"The 2016 World Health Organization classification of tumors of the central nervous system: a summary","volume":"131","author":"Louis","year":"2016","journal-title":"Acta Neuropathol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1093\/neuonc\/nou087","article-title":"The epidemiology of glioma in adults: a \u201cstate of the science\u201d review","volume":"16","author":"Ostrom","year":"2014","journal-title":"Neuro Oncol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s11060-011-0793-0","article-title":"Recent advances in the molecular understanding of glioblastoma","volume":"108","author":"Bleeker","year":"2012","journal-title":"J Neurooncol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"5591","DOI":"10.1242\/jcs.116392","article-title":"The tumor microenvironment at a glance","volume":"125","author":"Balkwill","year":"2012","journal-title":"J Cell Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.ccr.2012.02.022","article-title":"Accessories to the crime: functions of cells recruited to the tumor microenvironment","volume":"21","author":"Hanahan","year":"2012","journal-title":"Cancer Cell."},{"key":"B7","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3390\/medicina56010015","article-title":"Tumor microenvironment","volume":"56","author":"Arneth","year":"2019","journal-title":"Medicina."},{"key":"B8","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1097\/PPO.0000000000000118","article-title":"Imaging the tumor microenvironment","volume":"21","author":"LeBleu","year":"2015","journal-title":"Cancer J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1016\/j.cell.2020.05.007","article-title":"Interrogation of the microenvironmental landscape in brain tumors reveals disease-specific alterations of immune cells","volume":"181","author":"Klemm","year":"2020","journal-title":"Cell."},{"key":"B10","doi-asserted-by":"publisher","first-page":"578877","DOI":"10.3389\/fimmu.2020.578877","article-title":"Immune checkpoint targeted therapy in glioma: status and hopes","volume":"11","author":"Qi","year":"2020","journal-title":"Front Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"B12","doi-asserted-by":"publisher","first-page":"R47","DOI":"10.1186\/gb-2014-15-3-r47","article-title":"Clinical drug response can be predicted using baseline gene expression levels and in vitro drug sensitivity in cell lines","volume":"15","author":"Geeleher","year":"2014","journal-title":"Genome Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/s00401-007-0243-4","article-title":"The 2007 WHO classification of tumours of the central nervous system","volume":"114","author":"Louis","year":"2007","journal-title":"Acta Neuropathol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1093\/neuonc\/nox183","article-title":"Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications","volume":"20","author":"Malta","year":"2018","journal-title":"Neuro Oncol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2499","DOI":"10.1056\/NEJMoa1407279","article-title":"Glioma groups based on 1p\/19q, IDH, and TERT promoter mutations in tumors","volume":"372","author":"Eckel-Passow","year":"2015","journal-title":"N Engl J Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1007\/s11060-017-2386-z","article-title":"Serum amyloid A1 is upregulated in human glioblastoma","volume":"132","author":"Knebel","year":"2017","journal-title":"J Neuro Oncol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"5189","DOI":"10.1073\/pnas.1322357111","article-title":"Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis","volume":"111","author":"Lu","year":"2014","journal-title":"Proc Natl Acad Sci USA."},{"key":"B18","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.jprot.2012.06.022","article-title":"SAA1 is over-expressed in plasma of non small cell lung cancer patients with poor outcome after treatment with epidermal growth factor receptor tyrosine-kinase inhibitors","volume":"76","author":"Milan","year":"2012","journal-title":"J Proteomics."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1021\/pr101154j","article-title":"Identification and validation of SAA as a potential lung cancer biomarker and its involvement in metastatic pathogenesis of lung cancer","volume":"10","author":"Sung","year":"2011","journal-title":"J Proteome Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2641","DOI":"10.1016\/j.ajpath.2015.06.016","article-title":"Hepatic expression of serum amyloid A1 is induced by traumatic brain injury and modulated by telmisartan","volume":"185","author":"Villapol","year":"2015","journal-title":"Am J Pathol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1056\/NEJM199902113400607","article-title":"Acute-phase proteins and other systemic responses to inflammation","volume":"340","author":"Gabay","year":"1999","journal-title":"N Engl J Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1046\/j.1432-1327.1999.00657.x","article-title":"Serum amyloid A, the major vertebrate acute-phase reactant","volume":"265","author":"Uhlar","year":"1999","journal-title":"Eur J Biochem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.3892\/ol.2012.664","article-title":"Identification of serum amyloid A in the serum of gastric cancer patients by protein expression profiling","volume":"3","author":"Liu","year":"2012","journal-title":"Oncol Lett."},{"key":"B24","doi-asserted-by":"publisher","first-page":"332","DOI":"10.2478\/jomb-2018-0036","article-title":"Soluble sPD-L1 and serum amyloid A1 as potential biomarkers for lung cancer","volume":"38","author":"Jovanovi\u0107","year":"2019","journal-title":"J Med Biochem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1007\/s00011-013-0665-5","article-title":"Serum amyloid A, phospholipase A2-IIA and C-reactive protein as inflammatory biomarkers for prostate diseases","volume":"62","author":"Menschikowski","year":"2013","journal-title":"Inflamm Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1002\/cncr.24838","article-title":"Serum amyloid A: a novel biomarker for endometrial cancer","volume":"116","author":"Cocco","year":"2010","journal-title":"Cancer."},{"key":"B27","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1186\/1471-2407-12-365","article-title":"Elevated levels of serum amyloid A indicate poor prognosis in patients with esophageal squamous cell carcinoma","volume":"12","author":"Wang","year":"2012","journal-title":"BMC Cancer."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2199","DOI":"10.1200\/JCO.2008.18.0554","article-title":"Serum amyloid A as a prognostic marker in melanoma identified by proteomic profiling","volume":"27","author":"Findeisen","year":"2009","journal-title":"J Clin Oncol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2756","DOI":"10.7150\/jca.48419","article-title":"SAA1 knockdown promotes the apoptosis of glioblastoma cells via downregulation of AKT signaling","volume":"12","author":"Zhang","year":"2021","journal-title":"J Cancer."},{"key":"B30","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1002\/1878-0261.12196","article-title":"Serum amyloid A1 in combination with integrin \u03b1V\u03b23 increases glioblastoma cells mobility and progression","volume":"12","author":"Lin","year":"2018","journal-title":"Mol Oncol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"691811","DOI":"10.3389\/fimmu.2021.691811","article-title":"Immune infiltrating cells-derived risk signature based on large-scale analysis defines immune landscape and predicts immunotherapy responses in glioma tumor microenvironment","volume":"12","author":"Zhang","year":"2021","journal-title":"Front Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1002\/glia.10147","article-title":"Microglia in brain tumors","volume":"40","author":"Graeber","year":"2002","journal-title":"Glia."},{"key":"B33","doi-asserted-by":"publisher","first-page":"436","DOI":"10.3390\/ijms19020436","article-title":"When immune cells turn bad-tumor-associated microglia\/macrophages in glioma","volume":"19","author":"Roesch","year":"2018","journal-title":"Int J Mol Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"4603","DOI":"10.1016\/j.csbj.2021.08.019","article-title":"The molecular feature of macrophages in tumor immune microenvironment of glioma patients","volume":"19","author":"Zhang","year":"2021","journal-title":"Comput Struct Biotechnol J."},{"key":"B35","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1038\/nrc.2016.52","article-title":"Neutrophils in cancer: neutral no more","volume":"16","author":"Coffelt","year":"2016","journal-title":"Nat Rev Cancer."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.3390\/ijms21061954","article-title":"Role of neutrophils and myeloid-derived suppressor cells in glioma progression and treatment resistance","volume":"21","author":"Khan","year":"2020","journal-title":"Int J Mol Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s12943-022-01513-z","article-title":"Glioma targeted therapy: insight into future of molecular approaches","volume":"21","author":"Yang","year":"2022","journal-title":"Mol Cancer."},{"key":"B38","doi-asserted-by":"publisher","first-page":"4520","DOI":"10.1038\/s41467-020-18298-8","article-title":"Collagen promotes anti-PD-1\/PD-L1 resistance in cancer through LAIR1-dependent CD8(+) T cell exhaustion","volume":"11","author":"Peng","year":"2020","journal-title":"Nat Commun."},{"key":"B39","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1002\/path.5080","article-title":"Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules","volume":"245","author":"He","year":"2018","journal-title":"J Pathol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"7112","DOI":"10.18632\/aging.103065","article-title":"Identification of immunologic subtype and prognosis of GBM based on TNFSF14 and immune checkpoint gene expression profiling","volume":"12","author":"Long","year":"2020","journal-title":"Aging."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.18632\/aging.102706","article-title":"Elevated lymphocyte specific protein 1 expression is involved in the regulation of leukocyte migration and immunosuppressive microenvironment in glioblastoma","volume":"12","author":"Cao","year":"2020","journal-title":"Aging."},{"key":"B42","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1021\/bc400271x","article-title":"XAV939: from a small inhibitor to a potent drug bioconjugate when delivered by gold nanoparticles","volume":"25","author":"Afifi","year":"2014","journal-title":"Bioconjugate Chem."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2836","DOI":"10.3892\/or.2017.5991","article-title":"TGX-221 inhibits proliferation and induces apoptosis in human glioblastoma cells","volume":"38","author":"Yang","year":"2017","journal-title":"Oncology Rep."},{"key":"B44","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1007\/s11060-017-2533-6","article-title":"Report of safety of pulse dosing of lapatinib with temozolomide and radiation therapy for newly-diagnosed glioblastoma in a pilot phase II study","volume":"134","author":"Yu","year":"2017","journal-title":"J Neuro Oncol."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.905561\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T05:17:02Z","timestamp":1654838222000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.905561\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,10]]},"references-count":44,"alternative-id":["10.3389\/fneur.2022.905561"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2022.905561","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,10]]},"article-number":"905561"}}