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Review
. 2021 Sep 16;22(18):10018.
doi: 10.3390/ijms221810018.

C3G Protein, a New Player in Glioblastoma

Sara Manzano  1   2   3 , Alvaro Gutierrez-Uzquiza  1   2 , Paloma Bragado  1   2 , Angel M Cuesta  1   2 , Carmen Guerrero  4   5   6 , Almudena Porras  1   2
Affiliations
Review

C3G Protein, a New Player in Glioblastoma

Sara Manzano et al. Int J Mol Sci. .

Abstract

C3G (RAPGEF1) is a guanine nucleotide exchange factor (GEF) for GTPases from the Ras superfamily, mainly Rap1, although it also acts through GEF-independent mechanisms. C3G regulates several cellular functions. It is expressed at relatively high levels in specific brain areas, playing important roles during embryonic development. Recent studies have uncovered different roles for C3G in cancer that are likely to depend on cell context, tumour type, and stage. However, its role in brain tumours remained unknown until very recently. We found that C3G expression is downregulated in GBM, which promotes the acquisition of a more mesenchymal phenotype, enhancing migration and invasion, but not proliferation. ERKs hyperactivation, likely induced by FGFR1, is responsible for this pro-invasive effect detected in C3G silenced cells. Other RTKs (Receptor Tyrosine Kinases) are also dysregulated and could also contribute to C3G effects. However, it remains undetermined whether Rap1 is a mediator of C3G actions in GBM. Various Rap1 isoforms can promote proliferation and invasion in GBM cells, while C3G inhibits migration/invasion. Therefore, other RapGEFs could play a major role regulating Rap1 activity in these tumours. Based on the information available, C3G could represent a new biomarker for GBM diagnosis, prognosis, and personalised treatment of patients in combination with other GBM molecular markers. The quantification of C3G levels in circulating tumour cells (CTCs) in the cerebrospinal liquid and/or circulating fluids might be a useful tool to improve GBM patient treatment and survival.

Keywords: C3G; Rap; glioblastoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
C3G structure and isoforms. C3G domains from N-terminal to C-terminal: E-cadherin-binding domain and REM-interacting region; SH3-binding proline-riche domains (P0–P4) and autoinhibitory region (AIR); REM and CDC25H, both responsible for C3G GEF activity. The asterisk indicates Tyr504, the most well-established residue susceptible of phosphorylation. In isoforms with more amino acids than isoform A, inserts are included in purple.
Figure 2
Figure 2
Role of C3G in GBM cells dissemination as compared to other tumour types. (1) C3G levels are high in healthy brain and they decrease along GBM progression [63]. (2) C3G knock-down enhances migration/invasion of GBM cells in a similar way that it does in other tumours [63]. Nevertheless, the mechanisms governing this pro-invasive effect are diverse. In GBM, ERKs are overactivated when C3G is downregulated, likely induced by the increased activation of FGF2-FGFR1 and other RTKs, which enhances invasion (left panel). (3) C3G is also a negative regulator of migration/invasion in other tumours, but not in all cancer types (right panel) [55,57,58]. In GBM, C3G is downregulated and this plays an important role enhancing tumour aggressiveness [63]. GBM: glioblastoma; CRC: colorectal carcinoma; HCC: hepatocellular carcinoma.
Figure 3
Figure 3
RAPGEF1 mRNA levels in GBM patient tumour samples compared with healthy brain. Analysis of RAPGEF1 expression in control (n = 5) and GBM patient samples (n = 166) using data from the TCGA database. RAPGEF1 mRNA levels normalised with ACTB (left panel) or GUSB (right panel). U-Mann–Whitney test was used to compare the data and p values are shown.
Figure 4
Figure 4
Role played by C3G in GBM tumour growth compared to other tumourigenic processes. In GBM, C3G knock-down increases the number of foci, cell scattering, tumour size, stroma infiltration, and angiogenesis, while decreases cell density, proliferation, and the number of tumour cells within the tumour (left panel). This differs from its actions in other tumours (right panel) [31,49,50,55,57,60]. GBM: glioblastoma; α-SMA: α-smooth muscle actin; CRC: colorectal carcinoma; HCC: hepatocellular carcinoma; CML: chronic myeloid leukaemia.
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