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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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E-cadherin staining is reduced in the epithelial cells of colon mucosa in UC, and returns to normal level after anti-inflammatory therapy. Immunostaining with anti-E-cadherin antibodies, revealed by a peroxidase/DAB enzymatic reaction. In normal mucosa, all the epithelial cells of the crypts and the surface exhibited an intense staining at their boundaries (scale bars=80 μm (a), 20 μm (c)). In UC mucosa, the staining intensity appeared to be strongly reduced in some zones (scale bars=80 μm (b), 20 μm (d)). Arrows indicate epithelial cells with low or nil E-cadherin staining. After anti-inflammatory therapy E-cadherin immunostaining was superimposable to that of normal colon mucosa (scale bar=80 μm (e)). Hematoxylin counterstaining.
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fig6: E-cadherin staining is reduced in the epithelial cells of colon mucosa in UC, and returns to normal level after anti-inflammatory therapy. Immunostaining with anti-E-cadherin antibodies, revealed by a peroxidase/DAB enzymatic reaction. In normal mucosa, all the epithelial cells of the crypts and the surface exhibited an intense staining at their boundaries (scale bars=80 μm (a), 20 μm (c)). In UC mucosa, the staining intensity appeared to be strongly reduced in some zones (scale bars=80 μm (b), 20 μm (d)). Arrows indicate epithelial cells with low or nil E-cadherin staining. After anti-inflammatory therapy E-cadherin immunostaining was superimposable to that of normal colon mucosa (scale bar=80 μm (e)). Hematoxylin counterstaining.

Mentions: We then visualized and analyzed the expression of E-cadherin in histological sections using the immunoperoxidase and immunofluorescence techniques. The analysis of E-cadherin expression using the immunoperoxidase technique indicated that the control mucosa samples were characterized by an intense signal, perfectly decorating the boundaries of all the epithelial cells in the crypts and on the surface (Figures 6a and c). Regarding UC samples, a focal reduction of the signal was observed (Figure 6b). Furthermore, in many crypts, whereas some clusters of epithelial cells appeared to exhibit E-cadherin staining, the contiguous epithelial cells were completely unstained (Figure 6d). In colon samples from patients treated with anti-inflammatory drugs, E-cadherin expression pattern was superimposable to that of normal, control colonic mucosa (Figure 6e). The same results were obtained with the immunofluorescence analysis (Supplementary Figures 12a–e).


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)

E-cadherin staining is reduced in the epithelial cells of colon mucosa in UC, and returns to normal level after anti-inflammatory therapy. Immunostaining with anti-E-cadherin antibodies, revealed by a peroxidase/DAB enzymatic reaction. In normal mucosa, all the epithelial cells of the crypts and the surface exhibited an intense staining at their boundaries (scale bars=80 μm (a), 20 μm (c)). In UC mucosa, the staining intensity appeared to be strongly reduced in some zones (scale bars=80 μm (b), 20 μm (d)). Arrows indicate epithelial cells with low or nil E-cadherin staining. After anti-inflammatory therapy E-cadherin immunostaining was superimposable to that of normal colon mucosa (scale bar=80 μm (e)). Hematoxylin counterstaining.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150990&req=5

fig6: E-cadherin staining is reduced in the epithelial cells of colon mucosa in UC, and returns to normal level after anti-inflammatory therapy. Immunostaining with anti-E-cadherin antibodies, revealed by a peroxidase/DAB enzymatic reaction. In normal mucosa, all the epithelial cells of the crypts and the surface exhibited an intense staining at their boundaries (scale bars=80 μm (a), 20 μm (c)). In UC mucosa, the staining intensity appeared to be strongly reduced in some zones (scale bars=80 μm (b), 20 μm (d)). Arrows indicate epithelial cells with low or nil E-cadherin staining. After anti-inflammatory therapy E-cadherin immunostaining was superimposable to that of normal colon mucosa (scale bar=80 μm (e)). Hematoxylin counterstaining.
Mentions: We then visualized and analyzed the expression of E-cadherin in histological sections using the immunoperoxidase and immunofluorescence techniques. The analysis of E-cadherin expression using the immunoperoxidase technique indicated that the control mucosa samples were characterized by an intense signal, perfectly decorating the boundaries of all the epithelial cells in the crypts and on the surface (Figures 6a and c). Regarding UC samples, a focal reduction of the signal was observed (Figure 6b). Furthermore, in many crypts, whereas some clusters of epithelial cells appeared to exhibit E-cadherin staining, the contiguous epithelial cells were completely unstained (Figure 6d). In colon samples from patients treated with anti-inflammatory drugs, E-cadherin expression pattern was superimposable to that of normal, control colonic mucosa (Figure 6e). The same results were obtained with the immunofluorescence analysis (Supplementary Figures 12a–e).

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