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Interleukin 6 downregulates p53 expression and activity by stimulating ribosome biogenesis: a new pathway connecting inflammation to cancer.

Brighenti E, Calabrese C, Liguori G, Giannone FA, Trerè D, Montanaro L, Derenzini M - Oncogene (2014)

Bottom Line: The p53 downregulation induced the acquisition of cellular phenotypic changes characteristic of epithelial-mesenchymal transition, such as a reduced level of E-cadherin expression, increased cell invasiveness and a decreased response to cytotoxic stresses.We found that these changes also occurred in colon epithelial cells of patients with ulcerative colitis, a very representative example of chronic inflammation at high risk for tumor development.Taken together, the present results highlight a new mechanism that may link chronic inflammation to cancer, based on p53 downregulation, which is activated by the enhancement of rRNA transcription upon IL-6 exposure.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna, Italy.

ABSTRACT
Chronic inflammation is an established risk factor for the onset of cancer, and the inflammatory cytokine IL-6 has a role in tumorigenesis by enhancing proliferation and hindering apoptosis. As factors stimulating proliferation also downregulate p53 expression by enhancing ribosome biogenesis, we hypothesized that IL-6 may cause similar changes in inflamed tissues, thus activating a mechanism that favors neoplastic transformation. Here, we showed that IL-6 downregulated the expression and activity of p53 in transformed and untransformed human cell lines. This was the consequence of IL-6-dependent stimulation of c-MYC mRNA translation, which was responsible for the upregulation of rRNA transcription. The enhanced rRNA transcription stimulated the MDM2-mediated proteasomal degradation of p53, by reducing the availability of ribosome proteins for MDM2 binding. The p53 downregulation induced the acquisition of cellular phenotypic changes characteristic of epithelial-mesenchymal transition, such as a reduced level of E-cadherin expression, increased cell invasiveness and a decreased response to cytotoxic stresses. We found that these changes also occurred in colon epithelial cells of patients with ulcerative colitis, a very representative example of chronic inflammation at high risk for tumor development. Histochemical and immunohistochemical analysis of colon biopsy samples showed an upregulation of ribosome biogenesis, a reduced expression of p53, together with a focal reduction or absence of E-cadherin expression in chronic colitis in comparison with normal mucosa samples. These changes disappeared after treatment with anti-inflammatory drugs. Taken together, the present results highlight a new mechanism that may link chronic inflammation to cancer, based on p53 downregulation, which is activated by the enhancement of rRNA transcription upon IL-6 exposure.

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Ribosome biogenesis is upregulated in the epithelial cells of colon mucosa in UC, and returns to normal level after anti-inflammatory therapy. (a–g) Sections from histological routinely processed samples of human colon after the silver staining procedure for the selective visualization of nucleoli. At low magnification, the architecture of the normal (a) and UC mucosa (b) is perfectly recognizable. Note the higher cellularity in the lamina propria of the mucosa with UC, in comparison with the normal mucosa; *indicates lamina propria; scale bar=100 μm. At higher magnification, the nucleoli appeared to be darkly stained. The size of nucleoli of the epithelial cells lining the crypts of the normal mucosa (c) is smaller (mean nucleolar size=2.33±1.05 μm2) than that of the epithelial cell nucleoli in UC (mean nucleolar size=4.55±1.77 μm2) (d), P<0.0001. The same is true for the epithelial cells of the mucosal surface (1.27±0.44 μm2 vs 5.19±2.27 μm2, P<0.0001) (cross refer (e) with (f)). Scale bar=10 μm. In patients with UC treated with anti-inflammatory drugs (g) the hypercellularity was no longer present in the lamina propria (Scale bar=70 μm). Insets: the nucleoli of the epithelial cells lining the crypts and the surface of the mucosa exhibited the same size as that of the nucleoli in the normal mucosa, crypt cell nucleoli exhibiting a size of 2.45±0.99 μm2 and the surface epithelial cell nucleoli a size of 1.22±0.65 μm2. Scale bar=10 μm.
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fig4: Ribosome biogenesis is upregulated in the epithelial cells of colon mucosa in UC, and returns to normal level after anti-inflammatory therapy. (a–g) Sections from histological routinely processed samples of human colon after the silver staining procedure for the selective visualization of nucleoli. At low magnification, the architecture of the normal (a) and UC mucosa (b) is perfectly recognizable. Note the higher cellularity in the lamina propria of the mucosa with UC, in comparison with the normal mucosa; *indicates lamina propria; scale bar=100 μm. At higher magnification, the nucleoli appeared to be darkly stained. The size of nucleoli of the epithelial cells lining the crypts of the normal mucosa (c) is smaller (mean nucleolar size=2.33±1.05 μm2) than that of the epithelial cell nucleoli in UC (mean nucleolar size=4.55±1.77 μm2) (d), P<0.0001. The same is true for the epithelial cells of the mucosal surface (1.27±0.44 μm2 vs 5.19±2.27 μm2, P<0.0001) (cross refer (e) with (f)). Scale bar=10 μm. In patients with UC treated with anti-inflammatory drugs (g) the hypercellularity was no longer present in the lamina propria (Scale bar=70 μm). Insets: the nucleoli of the epithelial cells lining the crypts and the surface of the mucosa exhibited the same size as that of the nucleoli in the normal mucosa, crypt cell nucleoli exhibiting a size of 2.45±0.99 μm2 and the surface epithelial cell nucleoli a size of 1.22±0.65 μm2. Scale bar=10 μm.

Mentions: In order to evaluate whether an upregulation of rRNA transcriptional activity occurred in the epithelial cells of colonic mucosa from patients with UC, we measured the nucleolar size of these cells in histological sections selectively stained by silver for the argyrophilic nucleolar organizer region (AgNOR) proteins. This technique makes it possible to precisely evaluate the nucleolar size.28 As the nucleolar size is closely and directly related to rRNA transcription activity,15 we were able to obtain information on whether UC resulted in changes in the ribosome biogenesis rate. After silver staining, the histological characteristics of the normal colonic mucosa are perfectly recognized (Figure 4a). Colonic mucosa with UC appears to be characterized by a diffuse, mainly mononuclear inflammatory infiltrate in the lamina propria (Figure 4b). At a higher magnification, it is possible to observe that the epithelial cells of normal crypts exhibit small nucleoli (Figure 4c), whereas in crypt cells of UC they exhibited much larger nucleoli (Figure 4d). Morphometric analysis and statistical evaluation on normal and UC samples confirmed that in inflamed mucosa the size of crypt cell nucleoli was much larger than that of normal cell nucleoli. Hypertrophic nucleoli also characterized the surface epithelial cells of UC mucosa when compared with those of normal mucosa (Figures 4e and f). After treatment with anti-inflammatory drugs, the nucleolar size was reduced to the values of the epithelium of normal, control colonic mucosa (Figure 4g).


Interleukin 6 downregulates p53 expression and activity by stimulating ribosome biogenesis: a new pathway connecting inflammation to cancer.

Brighenti E, Calabrese C, Liguori G, Giannone FA, Trerè D, Montanaro L, Derenzini M - Oncogene (2014)

Ribosome biogenesis is upregulated in the epithelial cells of colon mucosa in UC, and returns to normal level after anti-inflammatory therapy. (a–g) Sections from histological routinely processed samples of human colon after the silver staining procedure for the selective visualization of nucleoli. At low magnification, the architecture of the normal (a) and UC mucosa (b) is perfectly recognizable. Note the higher cellularity in the lamina propria of the mucosa with UC, in comparison with the normal mucosa; *indicates lamina propria; scale bar=100 μm. At higher magnification, the nucleoli appeared to be darkly stained. The size of nucleoli of the epithelial cells lining the crypts of the normal mucosa (c) is smaller (mean nucleolar size=2.33±1.05 μm2) than that of the epithelial cell nucleoli in UC (mean nucleolar size=4.55±1.77 μm2) (d), P<0.0001. The same is true for the epithelial cells of the mucosal surface (1.27±0.44 μm2 vs 5.19±2.27 μm2, P<0.0001) (cross refer (e) with (f)). Scale bar=10 μm. In patients with UC treated with anti-inflammatory drugs (g) the hypercellularity was no longer present in the lamina propria (Scale bar=70 μm). Insets: the nucleoli of the epithelial cells lining the crypts and the surface of the mucosa exhibited the same size as that of the nucleoli in the normal mucosa, crypt cell nucleoli exhibiting a size of 2.45±0.99 μm2 and the surface epithelial cell nucleoli a size of 1.22±0.65 μm2. Scale bar=10 μm.
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fig4: Ribosome biogenesis is upregulated in the epithelial cells of colon mucosa in UC, and returns to normal level after anti-inflammatory therapy. (a–g) Sections from histological routinely processed samples of human colon after the silver staining procedure for the selective visualization of nucleoli. At low magnification, the architecture of the normal (a) and UC mucosa (b) is perfectly recognizable. Note the higher cellularity in the lamina propria of the mucosa with UC, in comparison with the normal mucosa; *indicates lamina propria; scale bar=100 μm. At higher magnification, the nucleoli appeared to be darkly stained. The size of nucleoli of the epithelial cells lining the crypts of the normal mucosa (c) is smaller (mean nucleolar size=2.33±1.05 μm2) than that of the epithelial cell nucleoli in UC (mean nucleolar size=4.55±1.77 μm2) (d), P<0.0001. The same is true for the epithelial cells of the mucosal surface (1.27±0.44 μm2 vs 5.19±2.27 μm2, P<0.0001) (cross refer (e) with (f)). Scale bar=10 μm. In patients with UC treated with anti-inflammatory drugs (g) the hypercellularity was no longer present in the lamina propria (Scale bar=70 μm). Insets: the nucleoli of the epithelial cells lining the crypts and the surface of the mucosa exhibited the same size as that of the nucleoli in the normal mucosa, crypt cell nucleoli exhibiting a size of 2.45±0.99 μm2 and the surface epithelial cell nucleoli a size of 1.22±0.65 μm2. Scale bar=10 μm.
Mentions: In order to evaluate whether an upregulation of rRNA transcriptional activity occurred in the epithelial cells of colonic mucosa from patients with UC, we measured the nucleolar size of these cells in histological sections selectively stained by silver for the argyrophilic nucleolar organizer region (AgNOR) proteins. This technique makes it possible to precisely evaluate the nucleolar size.28 As the nucleolar size is closely and directly related to rRNA transcription activity,15 we were able to obtain information on whether UC resulted in changes in the ribosome biogenesis rate. After silver staining, the histological characteristics of the normal colonic mucosa are perfectly recognized (Figure 4a). Colonic mucosa with UC appears to be characterized by a diffuse, mainly mononuclear inflammatory infiltrate in the lamina propria (Figure 4b). At a higher magnification, it is possible to observe that the epithelial cells of normal crypts exhibit small nucleoli (Figure 4c), whereas in crypt cells of UC they exhibited much larger nucleoli (Figure 4d). Morphometric analysis and statistical evaluation on normal and UC samples confirmed that in inflamed mucosa the size of crypt cell nucleoli was much larger than that of normal cell nucleoli. Hypertrophic nucleoli also characterized the surface epithelial cells of UC mucosa when compared with those of normal mucosa (Figures 4e and f). After treatment with anti-inflammatory drugs, the nucleolar size was reduced to the values of the epithelium of normal, control colonic mucosa (Figure 4g).

Bottom Line: The p53 downregulation induced the acquisition of cellular phenotypic changes characteristic of epithelial-mesenchymal transition, such as a reduced level of E-cadherin expression, increased cell invasiveness and a decreased response to cytotoxic stresses.We found that these changes also occurred in colon epithelial cells of patients with ulcerative colitis, a very representative example of chronic inflammation at high risk for tumor development.Taken together, the present results highlight a new mechanism that may link chronic inflammation to cancer, based on p53 downregulation, which is activated by the enhancement of rRNA transcription upon IL-6 exposure.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna, Italy.

ABSTRACT
Chronic inflammation is an established risk factor for the onset of cancer, and the inflammatory cytokine IL-6 has a role in tumorigenesis by enhancing proliferation and hindering apoptosis. As factors stimulating proliferation also downregulate p53 expression by enhancing ribosome biogenesis, we hypothesized that IL-6 may cause similar changes in inflamed tissues, thus activating a mechanism that favors neoplastic transformation. Here, we showed that IL-6 downregulated the expression and activity of p53 in transformed and untransformed human cell lines. This was the consequence of IL-6-dependent stimulation of c-MYC mRNA translation, which was responsible for the upregulation of rRNA transcription. The enhanced rRNA transcription stimulated the MDM2-mediated proteasomal degradation of p53, by reducing the availability of ribosome proteins for MDM2 binding. The p53 downregulation induced the acquisition of cellular phenotypic changes characteristic of epithelial-mesenchymal transition, such as a reduced level of E-cadherin expression, increased cell invasiveness and a decreased response to cytotoxic stresses. We found that these changes also occurred in colon epithelial cells of patients with ulcerative colitis, a very representative example of chronic inflammation at high risk for tumor development. Histochemical and immunohistochemical analysis of colon biopsy samples showed an upregulation of ribosome biogenesis, a reduced expression of p53, together with a focal reduction or absence of E-cadherin expression in chronic colitis in comparison with normal mucosa samples. These changes disappeared after treatment with anti-inflammatory drugs. Taken together, the present results highlight a new mechanism that may link chronic inflammation to cancer, based on p53 downregulation, which is activated by the enhancement of rRNA transcription upon IL-6 exposure.

Show MeSH
Related in: MedlinePlus