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. 2019 Oct 10;10:2366.
doi: 10.3389/fimmu.2019.02366. eCollection 2019.

Prognostic Implications of the Complement Protein C1q in Gliomas

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Free PMC article

Prognostic Implications of the Complement Protein C1q in Gliomas

Alessandro Mangogna et al. Front Immunol. .
Free PMC article

Abstract

The contribution of the complement system in the pathophysiology of brain cancers has been recently considered in light of its well-known involvement in carcinogenesis. Complement system represents an important component of the inflammatory response, which acts as a functional bridge between the innate and adaptive immune response. C1q, the first recognition subcomponent of the complement classical pathway, has recently been shown to be involved in a range of pathophysiological functions that are not dependent on complement activation. C1q is expressed in the microenvironment of various types of human tumors, including melanoma, prostate, mesothelioma, and ovarian cancers, where it can exert a protective or a harmful effect on cancer progression. Despite local synthesis of C1q in the central nervous system, the involvement of C1q in glioma pathogenesis has been poorly investigated. We, therefore, performed a bioinformatics analysis, using Oncomine dataset and UALCAN database in order to assess whether the expression of the genes encoding for the three chains of C1q (C1qA, C1qB, and C1qC) could serve as a potential prognostic marker for gliomas. The obtained results were then validated using an independent glioma cohort from the Chinese Glioma Genome Atlas datasets. Our bioinformatics analysis, coupled with immunohistochemistry and fluorescence microscopy, appears to suggest a positive correlation between higher levels of C1q expression and unfavorable prognosis in a diverse grade of gliomas.

Keywords: C1q complement; bioinformatics analysis; gliomas; prognostic significance of C1q; survival probability.

Figures

Figure 1
Figure 1
C1qA, C1qB, and C1qC expression in gliomas. Sun's dataset was used for bioinformatics analysis to explore C1qA and C1qB mRNAs expression in the glioblastoma multiforme, whereas Bredel 2's dataset was used for bioinformatics analysis to evaluate C1qC mRNA. A higher expression of the three chains was detectable in glioblastoma multiforme compared to normal brain tissue. GBM, glioblastoma multiforme.
Figure 2
Figure 2
Pathological significance of C1q expression in gliomas. According to the UALCAN database analysis, C1qA, C1qB, and C1qC mRNAs expression were negatively linked to a survival probability in patients with LGGs (grade-II and -III) (A), whereas no correlation in patients with GBM (grade-IV) (B). LGGs, low-grade gliomas; GBM, glioblastoma multiforme.
Figure 3
Figure 3
Pathological significance of C1q expression in gliomas. According to the CGGA database analysis, C1qA, C1qB, and C1qC mRNAs expression were negatively linked to a survival probability in patients with grade-III and GBM. H, high expression; L, low expression.
Figure 4
Figure 4
Representative immunohistochemical analysis of C1q in low (A,B) and high grade (C,D) gliomas showing a high expression in both histotypes regardless of grade. C1q results mainly expressed by macrophages and the vascular stroma (see arrows). C1q expression in the endothelial cells is shown in panels (E,F) (see arrows, low, and high magnification). Polymer detection system with AEC (red) chromogen; scale bars, 50 μm.
Figure 5
Figure 5
Representative immunohistochemical analysis of C3d and C4d complement activation products in low grade (A,D) and high grade (B,E) gliomas. C3d and C4d specific staining is segregated in the blood vessels, while the tumor tissues are negative. Liver staining (C,F) represents the antigen (tissue) control. Polymer detection system with AEC (red) chromogen; scale bars, 50 μm.
Figure 6
Figure 6
Representative microphotographs of double immunofluorescence for C1q (green signal) and CD68 (red signal) in FFPE sections of low (A) and high (B) grade gliomas confirming the macrophage nature of C1q expressing monocytoid elements. The cell nuclei were stained with DAPI; scale bars, 10 μm.
Figure 7
Figure 7
Representative microphotographs of double immunofluorescence for C1q (red signal) and CD163 (green signal) in FFPE sections of low (A) and high (B) grade gliomas confirming the M2-polarization of macrophages expressing C1q. The cell nuclei were stained with DAPI; scale bars, 10 μm.

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