GBP-1 acts as a tumor suppressor in colorectal cancer cells

Abstract

The human guanylate-binding protein 1 (GBP-1) is among the proteins the most highly induced by interferon-γ (IFN-γ) in every cell type investigated as yet. In vivo, GBP-1 expression is associated with the presence of inflammation and has been observed in autoimmune diseases, inflammatory bowel diseases (IBD) and cancer. In colorectal carcinoma (CRC), the expression of GBP-1 in the desmoplastic stroma has been previously reported to correlate with the presence of an IFN-γ-dominated T helper type 1 (Th1) micromilieu and with an increased cancer-related 5-year survival. In the present study, the analysis of GBP-1 expression in a series of 185 CRCs by immunohistochemistry confirmed that GBP-1 is expressed in stroma cells of CRCs and revealed a significantly less frequent expression in tumor cells, which was contradictory with the broad inducibility of GBP-1. Furthermore, three of six CRC cell lines treated with IFN-γ were unable to express GBP-1 indicating that colorectal tumor cells tend to downregulate GBP-1. On the contrary, non-transformed colon epithelial cells strongly expressed GBP-1 in vitro in presence of IFN-γ and in vivo in inflammatory bowel diseases. Reconstitution of GBP-1 expression in a negative CRC cell line inhibited cell proliferation, migration and invasion. Using RNA interference, we showed that GBP-1 mediates the antitumorigenic effects of IFN-γ in CRC cells. In addition, GBP-1 was able to inhibit tumor growth in vivo. Altogether, these results suggested that GBP-1 acts directly as a tumor suppressor in CRC and the loss of GBP-1 expression might indicate tumor evasion from the IFN-γ-dominated Th1 immune response.

Gamma Interferon-Induced Guanylate Binding Protein 1 Is a Novel Actin Cytoskeleton Remodeling Factor

“…Similar antipathogen effects have been observed with mouse GBPs (mGBPs), indicating that GBPs exert conserved functions in humans and rodents (9,(31)(32)(33). In addition, GBP-1 is both necessary and sufficient for the inhibitory effects of IFN-␥ on cell proliferation, migration, and invasion, as shown in endothelial cells and epithelial tumor cells (17,19,(34)(35)(36)(37). Of note, the putative murine homologue of human GBP-1, mGBP-2, has also been shown to inhibit cell motility (38).…”

“…Furthermore, an expression vector for the GFP-GBP-1 fusion protein (F-GFP-GBP-1) was generated with the pMCV1.4 construct as previously described (42). Additionally, the sequence of GBP-1 was inserted in frame into the pMCV2.2-Flag vector using the EcoRI restriction site (17).…”

“…In addition, IFN-␥ is an important trigger of antitumoral immune responses (2,(10)(11)(12)(13)(14). The direct antitumorigenic activity of IFN-␥ on tumor cells includes the induction of apoptosis (15,16) and the inhibition of cell proliferation, migration, and invasion (3,(17)(18)(19)(20).…”

Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

“…A recent report showed that mGBP2 and mGBP5 could promote bacteriolysis by controlling the activation of the inflammasome protein, AIM2, in mouse bone marrow-derived macrophages (36). In human cells, hGBP1 shows one of the highest induction levels in response to IFN-γ stimulation (37), which has been shown to be associated with viral infections, inflammatory bowel diseases, glioblastoma, and cutaneous lupus erythematosus (38)(39)(40)(41).…”

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

“…33 In colorectal cancer, GBP1 overexpression in tumor stroma inhibits tumor growth and correlates with improved survival. 34,35 The functions of other GBPs are less clear although animal and in-vitro models suggest a protective role in controlling infection and autoimmunity as GBPs are essential for formation of the inflammasome complex. 36 The inflammasome complex promotes inflammatory cell death through activation of cysteine protease caspase-1 and is purported to have tumor suppressive effects in some studies.…”