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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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The p53 expression is downregulated in the epithelial cells of the colon mucosa in UC, and returns to normal level after anti-inflammatory therapy. (a–f) Histological sections from human colon treated with monoclonal anti-p53 antibodies visualized by the peroxidase/DAB enzymatic reaction. (a) Normal colon mucosa. A large number of epithelial cell nuclei in the deeper half portion of the crypts was brick-red stained, indicating a positive reaction for p53 accumulation. (b) Detail of (a), at higher magnification. (c) UC. Only a few epithelial cells appeared to be positively stained for p53. (d) Detail of (c), at higher magnification. (e) UC after anti-inflammatory therapy. The number of epithelial cell nuclei showing a positive p53 reaction was comparable to that of the epithelium of normal, control colonic mucosa. (f) Detail of (e), at higher magnification. Scale bar=100 μm (a, c and e). Scale bar=25 μm (b, d and f). Hematoxylin counterstaining.
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fig5: The p53 expression is downregulated in the epithelial cells of the colon mucosa in UC, and returns to normal level after anti-inflammatory therapy. (a–f) Histological sections from human colon treated with monoclonal anti-p53 antibodies visualized by the peroxidase/DAB enzymatic reaction. (a) Normal colon mucosa. A large number of epithelial cell nuclei in the deeper half portion of the crypts was brick-red stained, indicating a positive reaction for p53 accumulation. (b) Detail of (a), at higher magnification. (c) UC. Only a few epithelial cells appeared to be positively stained for p53. (d) Detail of (c), at higher magnification. (e) UC after anti-inflammatory therapy. The number of epithelial cell nuclei showing a positive p53 reaction was comparable to that of the epithelium of normal, control colonic mucosa. (f) Detail of (e), at higher magnification. Scale bar=100 μm (a, c and e). Scale bar=25 μm (b, d and f). Hematoxylin counterstaining.

Mentions: We then evaluated the expression of p53 in histological sections from control and inflamed colon mucosa biopsy samples. We found that in normal colon mucosa the labeling was present mainly in the epithelial cells of the deeper portion of the crypts (Figures 5a and b). The labeling index of epithelial cells within the crypts was 24.5 (±6.8 s.d.). Also, in the colon mucosa of patients with UC, labeled cells were mainly located in the deeper portion of the crypts (Figures 5c and d). However, the percentage of labeled cells was lower (labeling index=9.8±4.5 s.d.), thus indicating a downregulation of p53 expression in UC epithelial cells (P<0.01). These data are consistent with the recent observation reported by Risques et al.29 that p53 expression in human normal colon epithelial cells was higher, even though in a nonstatistically significant manner, than that of patients with UC in whom cancerous lesions had developed. After treatment with anti-inflammatory drugs, the percentage of labeled cells was found to be quite similar to that of normal, control colonic mucosa (27.2±7.9 s.d.) (Figures 5e and f). These changes were associated with quantitative variation of IL-6 expression in the inflammatory infiltrate. As shown in Supplementary Figure 11, the number of inflammatory cells immunostained for IL-6 was low in normal colon mucosa; it was increased in UC, and reverted to the normal colon value after treatment with anti-inflammatory drugs.


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)

The p53 expression is downregulated in the epithelial cells of the colon mucosa in UC, and returns to normal level after anti-inflammatory therapy. (a–f) Histological sections from human colon treated with monoclonal anti-p53 antibodies visualized by the peroxidase/DAB enzymatic reaction. (a) Normal colon mucosa. A large number of epithelial cell nuclei in the deeper half portion of the crypts was brick-red stained, indicating a positive reaction for p53 accumulation. (b) Detail of (a), at higher magnification. (c) UC. Only a few epithelial cells appeared to be positively stained for p53. (d) Detail of (c), at higher magnification. (e) UC after anti-inflammatory therapy. The number of epithelial cell nuclei showing a positive p53 reaction was comparable to that of the epithelium of normal, control colonic mucosa. (f) Detail of (e), at higher magnification. Scale bar=100 μm (a, c and e). Scale bar=25 μm (b, d and f). Hematoxylin counterstaining.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4150990&req=5

fig5: The p53 expression is downregulated in the epithelial cells of the colon mucosa in UC, and returns to normal level after anti-inflammatory therapy. (a–f) Histological sections from human colon treated with monoclonal anti-p53 antibodies visualized by the peroxidase/DAB enzymatic reaction. (a) Normal colon mucosa. A large number of epithelial cell nuclei in the deeper half portion of the crypts was brick-red stained, indicating a positive reaction for p53 accumulation. (b) Detail of (a), at higher magnification. (c) UC. Only a few epithelial cells appeared to be positively stained for p53. (d) Detail of (c), at higher magnification. (e) UC after anti-inflammatory therapy. The number of epithelial cell nuclei showing a positive p53 reaction was comparable to that of the epithelium of normal, control colonic mucosa. (f) Detail of (e), at higher magnification. Scale bar=100 μm (a, c and e). Scale bar=25 μm (b, d and f). Hematoxylin counterstaining.
Mentions: We then evaluated the expression of p53 in histological sections from control and inflamed colon mucosa biopsy samples. We found that in normal colon mucosa the labeling was present mainly in the epithelial cells of the deeper portion of the crypts (Figures 5a and b). The labeling index of epithelial cells within the crypts was 24.5 (±6.8 s.d.). Also, in the colon mucosa of patients with UC, labeled cells were mainly located in the deeper portion of the crypts (Figures 5c and d). However, the percentage of labeled cells was lower (labeling index=9.8±4.5 s.d.), thus indicating a downregulation of p53 expression in UC epithelial cells (P<0.01). These data are consistent with the recent observation reported by Risques et al.29 that p53 expression in human normal colon epithelial cells was higher, even though in a nonstatistically significant manner, than that of patients with UC in whom cancerous lesions had developed. After treatment with anti-inflammatory drugs, the percentage of labeled cells was found to be quite similar to that of normal, control colonic mucosa (27.2±7.9 s.d.) (Figures 5e and f). These changes were associated with quantitative variation of IL-6 expression in the inflammatory infiltrate. As shown in Supplementary Figure 11, the number of inflammatory cells immunostained for IL-6 was low in normal colon mucosa; it was increased in UC, and reverted to the normal colon value after treatment with anti-inflammatory drugs.

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