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S100A Gene Family: Immune-Related Prognostic Biomarkers and Therapeutic Targets for Low-Grade Glioma

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S100A Gene Family: Immune-Related Prognostic Biomarkers and Therapeutic Targets for Low-Grade Glioma www.aging-us.com AGING 2021, Vol. 13, No. 11 Research Paper S100A gene family: immune-related prognostic biomarkers and therapeutic targets for low-grade glioma Yu Zhang1,*, Xin Yang1,*, Xiao-Lin Zhu1,*, Hao Bai1, Zhuang-Zhuang Wang1, Jun-Jie Zhang1, Chun-Yan Hao2,&, Hu-Bin Duan1,3 1Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, P.R. China 2Department of Geriatrics, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, P.R. China 3Department of Neurosurgery, Lvliang People's Hospital, Lvliang, Shanxi 033000, P.R. China *Equal contribution Correspondence to: Hu-Bin Duan, Chun-Yan Hao; email: [email protected], https://orcid.org/0000-0003-2896-6926; [email protected] Keywords: S100A, low-grade glioma, prognosis, immune, mutation Abbreviations: LGG: low-grade glioma; GO: gene ontology; KEGG: kyoto encyclopedia of genes and genomes; PPI: protein- protein interaction Received: December 21, 2020 Accepted: May 13, 2021 Published: June 8, 2021 Copyright: © 2021 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Background: Despite the better prognosis given by surgical resection and chemotherapy in low-grade glioma (LGG), progressive transformation is still a huge concern. In this case, the S100A gene family, being capable of regulating inflammatory responses, can promote tumor development. Methods: The analysis was carried out via ONCOMINE, GEPIA, cBioPortal, String, GeneMANIA, WebGestalt, LinkedOmics, TIMER, CGGA, R 4.0.2 and immunohistochemistry. Results: S100A2, S100A6, S100A10, S100A11, and S100A16 were up-regulated and S100A1 and S100A13 were down-regulated in LGG compared to normal tissues. S100A3, S100A4, S100A8, and S100A9 expression was up- regulated during the progression of glioma grade. In addition, genetic variation of the S100A family was high in LGG, and the S100A family genes mostly function through IL-17 signaling pathway, S100 binding protein, and inflammatory responses. The TIMER database also revealed a relationship between gene expression and immune cell infiltration. High expression of S100A2, S100A3, S100A4, S100A6, S100A8, S100A9, S100A10, S100A11, S100A13, and S100A16 was significantly associated with poor prognosis in LGG patients. S100A family genes S100A2, S100A3, S100A6, S100A10, and S100A11 may be prognosis-related genes in LGG, and were significantly associated with IDH mutation and 1p19q codeletion. The immunohistochemical staining results also confirmed that S100A2, S100A3, S100A6, S100A10, and S100A11 expression was upregulated in LGG. Conclusion: The S100A family plays a vital role in LGG pathogenesis, presumably facilitating LGG progression via modulating inflammatory state and immune cell infiltration. INTRODUCTION relatively favorable prognosis [2–4]. However, in the process of glioma development, mutated genes Glioma is the most common type of intracranial tumor. accumulate and the tumor microenvironment changes, Low-grade glioma (LGG) is classified by the World and LGGs may slowly develop into high-grade gliomas Health Organization (WHO) into grade I and grade II (HGGs) [5–8]. Macrophages release inflammatory [1]. Currently, LGG is primarily treated with surgical substances that cause gliomas to appear more resection, radiotherapy, and chemotherapy, having a aggressive [9, 10]. In line with this evidence, there is a www.aging-us.com 15459 AGING hypothesis that regulation of the tumor immune process Gene mutations and PPI networks of S100A family may potentially play a role in the treatment of glioma in LGG [11]. However, there are currently many challenges in glioma immunotherapy. For example, gliomas Via the cBioPortal database, we analyzed genetic themselves secrete inhibitory cytokines, which leads to variation of the S100A family based on the LGG an immunosuppressive microenvironment [12, 13]. sample data from the TCGA database. The results are Moreover, the immune resistance of tumor cells in presented in Figure 3A. The mutation rate was 4% for gliomas is significantly increased, and immune cells may S100A2, S100A4, and S100A6, 5% for S100A1, transition from an anti-tumor phenotype to pro-tumor S100A3, S100A8, S100A9, S100A11, S100A13, and phenotype [14, 15]. Therefore, it is necessary to develop S100A14, and 6% for S100A10 and S100A16. appropriate targets as the operational points of glioma treatment. Secretion of S100A protein is detectable in We also performed PPI network analysis of the S100A the extracellular space and in certain body fluids, such as family via STRING and GeneMANIA to explore serum, urine, sputum, cerebrospinal fluid, and feces [16– potential protein interactions and to seek network- 18]. S100A family members are widely involved in a related genes. The PPI network identified by the variety of inflammatory disease regulatory processes, STRING database presented 12 S100A family gene including ischemic heart inflammation, Kawasaki nodes and 26 edges (Figure 3B). S100A family gene disease, eye inflammation, and chorioamnionitis, among functions were suggested to be related to the IL-17 others [19–23]. Multiple studies have shown that some signaling pathway, S100 protein binding, and of the S100A family members regulate tumor inflammatory responses. Furthermore, the GeneMANIA development by mediating tumor immune processes results also showed that the function of S100A family [24–27]. Therefore, we investigated the role of the genes (S100A1, S100A2, S100A3, S100A4, S100A6, S100A protein family in glioma pathology. S100A8, S100A9, S100A10, S100A11, S100A13, S100A14, S100A16) were mainly associated with S100 RESULTS protein binding, calcium ion binding, and calcium- dependent protein binding. S100A family protein Differential expression of S100A family genes in network-related genes included S100B, S100P, LGG ANXA2, FGF1, S100A12. S100A7, ANXA11, PLEKHF2, TRIM29, PEX5, IRAK1, GFAP, ANXA1, We retrieved 12 S100A family genes, including ANXA6, DES, FSHR, CSTA, PLN, PPIA, and S100A1, S100A2, S100A3, S100A4, S100A6, METAP2 (Figure 3C). S100A8, S100A9, S100A10, S100A11, S100A13, S100A14, and S100A16, and acquired their mRNA Enrichment analysis of S100A family genes in LGGs expression levels in various tumors and normal tissues via the ONCOMINE database. Results showed that We conducted GO functional annotation and KEGG compared to normal tissues, the expression of S100A3, pathway enrichment analysis of S100A family genes S100A4, S100A6, S100A8, S100A9, S100A10, (S100A1, S100A2, S100A3, S100A4, S100A6, S100A11, and S100A16 was upregulated in CNS S100A8, S100A9, S100A10, S100A11, S100A13, cancer tissues, while S100A1 and S100A13 were S100A14, S100A16) and protein network-related genes downregulated (Figure 1). (S100B, S100P, ANXA2, FGF1, S100A12, S100A7, ANXA11, PLEKHF2, TRIM29, PEX5, IRAK1, GFAP, We assessed differential expression of 12 S100A family ANXA1, ANXA6, DES, FSHR, CSTA, PLN, PPIA, genes across LGG, GBM, and normal tissues via the METAP2) based on the WebGestalt database (Table 1). GEPIA database Single Gene Analysis module. The The results show that at the BP level, these genes were results showed that S100A2, S100A6, S100A10, mainly enriched in granulocyte chemotaxis, granulocyte S100A11, and S100A16 were upregulated and S100A1 migration, leukocyte activation involved in immune and S100A13 were downregulated in LGG compared to response, cell activation involved in immune response, normal tissues (p<0.05). S100A2, S100A3, S100A4, leukocyte degranulation, myeloid cell activation S100A6, S100A8, S100A9, S100A10, S100A11, and involved in immune response, immune response, S100A16 were upregulated and S100A1 was myeloid leukocyte mediated immunity, cell chemotaxis, downregulated in GBM compared to normal tissues and innate immune response (Figure 4A). At the CC (p<0.05). There was no significant difference in the level, the genes were predominantly enriched in expression of S100A3, S100A4, S100A8, and S100A9 extracellular matrix, collagen-containing extracellular in LGGs compared with normal tissues. However, matrix, secretory granule lumen, cytoplasmic vesicle expression of these genes was upregulated during the lumen, vesicle lumen, cell-cell adherens junction, progression of glioma grade (Figure 2A–2L). cytoplasmic vesicle part, adherens junction, anchoring www.aging-us.com 15460 AGING Figure 1. Differential expression of S100A family genes in various types of tumors and normal tissues. Red: high expression level, darker color means higher expression level, blue: low expression level, darker color means lower expression level. Figure 2. Differential expression of S100A family genes in LGG, GBM and normal tissues. (A) S100A1, (B) S100A2, (C) S100A3, (D) S100A4, (E) S100A6, (F) S100A8, (G) S100A9, (H) S100A10, (I) S100A11, (J) S100A13, (K) S100A14, (L) S100A16. *P < 0.05. www.aging-us.com 15461 AGING junction, and secretory granule (Figure 4B). At the MF of S100A3 and S100A4 was SRF. The main level, the genes were enriched in calcium ion binding, transcription factor target of S100A10 and S100A11 calcium-dependent protein binding, RAGE receptor was IRF. And S100A13, S100A14 and S100A16 were binding, S100 protein binding, identical protein binding, respectively corresponding to MAX, E2F and YY1. The cadherin binding involved in cell-cell adhesion, protein top miRNA targets for S100A1,
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