S100A6 is a potential diagnostic and prognostic biomarker for human glioma

Hong,Bo; Zhang,Hui; Xiao,Yufei; Shen,Lingwei; Qian,Yun

doi:10.3892/ol.2023.14045

S100A6 is a potential diagnostic and prognostic biomarker for human glioma

Authors:
- Bo Hong
- Hui Zhang
- Yufei Xiao
- Lingwei Shen
- Yun Qian
View Affiliations

Affiliations: Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China, Department of Clinical Laboratory, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China, Department of Clinical Laboratory, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
Published online on: September 6, 2023 https://doi.org/10.3892/ol.2023.14045
Article Number: 458
Copyright: © Hong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

S100 calcium‑binding protein A6 (S100A6) is a protein that belongs to the S100 family. The present study aimed to investigate the function of S100A6 in the diagnosis and survival prediction of glioma and elucidated the potential processes affecting glioma development. The Cancer Genome Atlas database was searched to identify the relationship among S100A6 expression, immune cell infiltration, clinicopathological parameters and glioma prognosis. Several clinical cases were used to verify these findings. S100A6 gene expression was high in glioma tissues, suggesting its diagnostic significance. In particular, S100A6 upregulation in glioma tissues exhibited a significant and positive correlation with the World Health Organization (WHO) grade, histological type, age, sex, primary treatment outcomes, 1p/19q codeletion, isocitrate dehydrogenase (IDH) status, overall survival (OS), progression‑free interval and disease‑specific survival. Kaplan‑Meier and Cox regression analyses revealed that S100A6 gene expression can independently function as a risk factor affecting the prognosis of patients with glioma. Furthermore, Gene Ontology functional enrichment analysis revealed that S100A6 is implicated in immune responses and that the expression profiles of S100A6 are linked to the immune microenvironment. Furthermore, immunohistochemistry revealed that increased S100A6 protein levels are correlated with age, 1p/19q codeletion, IDH status, WHO grade and OS. The present findings suggest that increased S100A6 expression is an indicator of the dismal prognosis of patients with glioma and that it can be used as a potential diagnostic biomarker for this condition.

View Figures

View References

1	Ostrom QT, Price M, Neff C, Cioffi G, Waite KA, Kruchko C and Barnholtz-Sloan JS: CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2015–2019. Neuro Oncol. 24 (Suppl 5):S1–S95. 2022. View Article : Google Scholar
2	Wesseling P and Capper D: WHO 2016 classification of gliomas. Neuropathol Appl Neurobiol. 44:139–150. 2018. View Article : Google Scholar : PubMed/NCBI
3	Xu S, Tang L, Li X, Fan F and Liu Z: Immunotherapy for glioma: Current management and future application. Cancer Letters. 476:1–12. 2020. View Article : Google Scholar : PubMed/NCBI
4	Wen J, Chen W, Zhu Y and Zhang P: Clinical features associated with the efficacy of chemotherapy in patients with glioblastoma (GBM): A surveillance, epidemiology, and end results (SEER) analysis. BMC Cancer. 21:812021. View Article : Google Scholar : PubMed/NCBI
5	Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS and Khasraw M: Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 70:299–312. 2020. View Article : Google Scholar : PubMed/NCBI
6	Ramón Y, Cajal S, Sesé M, Capdevila C, Aasen T, De Mattos-Arruda L, Diaz-Cano SJ, Hernández-Losa J and Castellví J: Clinical implications of intratumor heterogeneity: Challenges and opportunities. J Mol Med (Berl). 98:161–177. 2020. View Article : Google Scholar
7	Binder DC, Ladomersky E, Lenzen A, Zhai L, Lauing KL, Otto-Meyer SD, Lukas RV and Wainwright DA: Lessons learned from rindopepimut treatment in patients with EGFRvIII-expressing glioblastoma. Transl Cancer Res. 7 (Suppl 4):S510–S513. 2018. View Article : Google Scholar : PubMed/NCBI
8	Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, Brandes AA, Taal W, Domont J, Idbaih A, et al: Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 377:1954–1963. 2017. View Article : Google Scholar : PubMed/NCBI
9	de la Fuente MI, Colman H, Rosenthal M, Van Tine BA, Levacic D, Walbert T, Gan HK, Vieito M, Milhem MM, Lipford K, et al: Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial. Neuro Oncol. 25:146–156. 2023. View Article : Google Scholar : PubMed/NCBI
10	Bale TA and Rosenblum MK: The 2021 WHO classification of tumors of the central nervous system: An update on pediatric low-grade gliomas and glioneuronal tumors. Brain Pathol. 32:e130602022. View Article : Google Scholar : PubMed/NCBI
11	Gonzalez LL, Garrie K and Turner MD: Role of S100 proteins in health and disease. Biochim Biophys Acta Mol Cell Res. 1867:1186772020. View Article : Google Scholar : PubMed/NCBI
12	Li Z, Tang M, Ling B, Liu S, Zheng Y, Nie C, Yuan Z, Zhou L, Guo G, Tong A and Wei Y: Increased expression of S100A6 promotes cell proliferation and migration in human hepatocellular carcinoma. J Mol Med (Berl). 92:291–303. 2014. View Article : Google Scholar : PubMed/NCBI
13	Li Y, Wagner ER, Yan Z, Wang Z, Luther G, Jiang W, Ye J, Wei Q, Wang J, Zhao L, et al: The calcium-binding protein S100A6 accelerates human osteosarcoma growth by promoting cell proliferation and inhibiting osteogenic differentiation. Cell Physiol Biochem. 37:2375–2392. 2015. View Article : Google Scholar : PubMed/NCBI
14	Chen X, Liu X, Lang H, Zhang S, Luo Y and Zhang J: S100 calcium-binding protein A6 promotes epithelial-mesenchymal transition through β-catenin in pancreatic cancer cell line. PLoS One. 10:e01213192015. View Article : Google Scholar : PubMed/NCBI
15	Wang XH, Zhang LH, Zhong XY, Xing XF, Liu YQ, Niu ZJ, Peng Y, Du H, Zhang GG, Hu Y, et al: S100A6 overexpression is associated with poor prognosis and is epigenetically up-regulated in gastric cancer. Am J Pathol. 177:586–597. 2010. View Article : Google Scholar : PubMed/NCBI
16	Li L, Pan Y, Mo X, Wei T, Song J, Luo M, Huang G, Teng C, Liang K, Mao N and Yang J: A novel metastatic promoter CEMIP and its downstream molecular targets and signaling pathway of cellular migration and invasion in SCLC cells based on proteome analysis. J Cancer Res Clin Oncol. 146:2519–2534. 2020. View Article : Google Scholar : PubMed/NCBI
17	Camby I, Nagy N, Lopes MB, Schäfer BW, Maurage CA, Ruchoux MM, Murmann P, Pochet R, Heizmann CW, Brotchi J, et al: Supratentorial pilocytic astrocytomas, astrocytomas, anaplastic astrocytomas and glioblastomas are characterized by a differential expression of S100 proteins. Brain Pathol. 9:1–19. 1999. View Article : Google Scholar : PubMed/NCBI
18	Camby I, Lefranc F, Titeca G, Neuci S, Fastrez M, Dedecken L, Schäfer BW, Brotchi J, Heizmann CW, Pochet R, et al: Differential expression of S100 calcium-binding proteins characterizes distinct clinical entities in both WHO grade II and III astrocytic tumours. Neuropathol Appl Neurobiol. 26:76–90. 2000. View Article : Google Scholar : PubMed/NCBI
19	Kucharczak J, Pannequin J, Camby I, Decaestecker C, Kiss R and Martinez J: Gastrin induces over-expression of genes involved in human U373 glioblastoma cell migration. Oncogene. 20:7021–7028. 2001. View Article : Google Scholar : PubMed/NCBI
20	Zhang Y, Yang X, Zhu XL, Bai H, Wang ZZ, Zhang JJ, Hao CY and Duan HB: S100A gene family: Immune-related prognostic biomarkers and therapeutic targets for low-grade glioma. Aging (Albany NY). 13:15459–15478. 2021. View Article : Google Scholar : PubMed/NCBI
21	Blum A, Wang P and Zenklusen JC: SnapShot: TCGA-analyzed tumors. Cell. 173:5302018. View Article : Google Scholar : PubMed/NCBI
22	Chin L, Hahn WC, Getz G and Meyerson M: Making sense of cancer genomic data. Genes Dev. 25:534–555. 2011. View Article : Google Scholar : PubMed/NCBI
23	Grossman RL, Heath AP, Ferretti V, Varmus HE, Lowy DR, Kibbe WA and Staudt LM: Toward a shared vision for cancer genomic data. N Engl J Med. 75:1109–1112. 2016. View Article : Google Scholar
24	Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, Morozova O, Newton Y, Radenbaugh A, Pagnotta SM, et al: Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell. 164:550–663. 2016. View Article : Google Scholar : PubMed/NCBI
25	Love MI, Huber W and Anders S: Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15:5502014. View Article : Google Scholar : PubMed/NCBI
26	Yan X, Hong B, Feng J, Jin Y, Chen M, Li F and Qian Y: B7-H4 is a potential diagnostic and prognostic biomarker in colorectal cancer and correlates with the epithelial-mesenchymal transition. BMC Cancer. 22:10532022. View Article : Google Scholar : PubMed/NCBI
27	Fan W, Song Y, Ren Z, Cheng X, Li P, Song H and Jia L: Glioma cells are resistant to inflammation-induced alterations of mitochondrial dynamics. Int J Oncol. 57:1293–1306. 2020. View Article : Google Scholar : PubMed/NCBI
28	Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, Kovatich AJ, Benz CC, Levine DA, Lee AV, et al: An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell. 173:400–416.e411. 2018. View Article : Google Scholar : PubMed/NCBI
29	Yu CH: Evaluation of diagnostic test, Medical statistics. Beijing: People's Medical Publishing House; pp. 164–178. 2002, (In Chinese).
30	Radin DP and Tsirka SE: Interactions between tumor cells, neurons, and microglia in the glioma microenvironment. Int J Mol Sci. 21:84762020. View Article : Google Scholar : PubMed/NCBI
31	Barthel L, Hadamitzky M, Dammann P, Schedlowski M, Sure U, Thakur BK and Hetze S: Glioma: molecular signature and crossroads with tumor microenvironment. Cancer Metastasis Rev. 41:53–75. 2022. View Article : Google Scholar : PubMed/NCBI
32	Filipek A and Leśniak W: S100A6 and its brain ligands in neurodegenerative disorders. Int J Mol Sci. 21:39792020. View Article : Google Scholar : PubMed/NCBI
33	Donato R, Sorci G and Giambanco I: S100a6 protein: functional roles. Cell Mol Life Sci. 74:2749–2760. 2017. View Article : Google Scholar : PubMed/NCBI
34	Hua X, Zhang H, Jia J, Chen S, Sun Y and Zhu X: Roles of S100 family members in drug resistance in tumors: Status and prospects. BioMed Pharmacother. 127:1101562020. View Article : Google Scholar : PubMed/NCBI
35	Hu Y, Zeng N, Ge Y, Wang D, Qin X, Zhang W, Jiang F and Liu Y: Identification of the shared gene signatures and biological mechanism in type 2 diabetes and pancreatic cancer. Front Endocrinol (Lausanne). 13:8477602022. View Article : Google Scholar : PubMed/NCBI
36	Zhao J, Huang Y, Song Y, Xie D, Hu M, Qiu H and Chu J: Diagnostic accuracy and potential covariates for machine learning to identify IDH mutations in glioma patients: Evidence from a meta-analysis. Eur Radiol. 30:4664–4674. 2020. View Article : Google Scholar : PubMed/NCBI
37	Ghouzlani A, Kandoussi S, Tall M, Reddy KP, Rafii S and Badou A: Immune checkpoint inhibitors in human glioma microenvironment. Front Immunol. 12:6794252021. View Article : Google Scholar : PubMed/NCBI
38	Lapointe S, Perry A and Butowski NA: Primary brain tumours in adults. Lancet. 392:432–446. 2018. View Article : Google Scholar : PubMed/NCBI
39	Wirths O, Breyhan H, Marcello A, Cotel MC, Bruck W and Bayer TA: Inflammatory changes are tightly associated with neurodegeneration in the brain and spinal cord of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiol Aging. 31:747–757. 2010. View Article : Google Scholar : PubMed/NCBI
40	Tong H, Wang L, Zhang K, Shi J, Wu Y, Bao Y and Wang C: Correction to: S100A6 activates kupffer cells via the p-P38 and p-JNK pathways to induce inflammation, mononuclear/macrophage infiltration sterile liver injury in mice. Inflammation. 46:5552023. View Article : Google Scholar : PubMed/NCBI
41	Liu Z, Zhang X, Chen M, Cao Q and Huang D: Effect of S100A6 over-expression on beta-catenin in endometriosis. J Obstet Gynaecol Res. 41:1457–1462. 2015. View Article : Google Scholar : PubMed/NCBI
42	Rijsewijk F, van Deemter L, Wagenaar E, Sonnenberg A and Nusse R: Transfection of the int-1 mammary oncogene in cuboidal RAC mammary cell line results in morphological transformation and tumorigenicity. EMBO J. 6:127–131. 1987. View Article : Google Scholar : PubMed/NCBI
43	Deberardinis RJ: Tumor microenvironment, metabolism, and immunotherapy. N Engl J Med. 382:869–871. 2020. View Article : Google Scholar : PubMed/NCBI
44	Chen F, Song J, Ye Z, Xu B, Cheng H, Zhang S and Sun X: Integrated analysis of cell cycle-related and immunity-related biomarker signatures to improve the prognosis prediction of lung adenocarcinoma. Front Oncol. 11:6668262021. View Article : Google Scholar : PubMed/NCBI
45	Li C, Jiang P, Wei S, Xu X and Wang J: Regulatory T cells in tumor microenvironment: New mechanisms, potential therapeutic strategies and future prospects. Mol Cancer. 19:1162020. View Article : Google Scholar : PubMed/NCBI
46	Erin N, Grahovac J, Brozovic A and Efferth T: Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance. Drug Resist Update. 53:1007152020. View Article : Google Scholar : PubMed/NCBI
47	Wei J, Chen P, Gupta P, Ott M, Zamler D, Kassab C, Bhat KP, Curran MA, de Groot JF and Heimberger AB: Immune biology of glioma-associated macrophages and microglia: Functional and therapeutic implications. Neuro Oncol. 22:180–194. 2020.PubMed/NCBI
48	Xia Y, Rao L, Yao H, Wang Z, Ning P and Chen X: Engineering macrophages for cancer immunotherapy and drug delivery. Adv Mater. 32:e20020542020. View Article : Google Scholar : PubMed/NCBI
49	Hambardzumyan D, Gutmann DH and Kettenmann H: The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 19:20–27. 2016. View Article : Google Scholar : PubMed/NCBI
50	Domingues P, González-Tablas M, Otero Á, Pascual D, Miranda D, Ruiz L, Sousa P, Ciudad J, Gonçalves JM, Lopes MC, et al: Tumor infiltrating immune cells in gliomas and meningiomas. Brain Behav Immun. 53:1–15. 2016. View Article : Google Scholar : PubMed/NCBI
51	Di W, Fan W, Wu F, Shi Z, Wang Z, Yu M, Zhai Y, Chang Y, Pan C, Li G, et al: Clinical characterization and immunosuppressive regulation of CD161 (KLRB1) in glioma through 916 samples. Cancer Sci. 113:756–769. 2022. View Article : Google Scholar : PubMed/NCBI
52	Cho A, McKelvey KJ, Lee A and Hudson AL: The intertwined fates of inflammation and coagulation in glioma. Mamm Genome. 29:806–816. 2018. View Article : Google Scholar : PubMed/NCBI