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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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Related in: MedlinePlus

Suggested pathway linking chronic inflammation to cancer. In inflamed tissues, such as colon mucosa with UC, a high amount of IL-6 is produced. IL-6 upregulates c-myc protein expression, which, in turn, enhances ribosome biogenesis. The enhanced ribosome biogenesis is responsible for an increased MDM2-mediated p53 degradation. This, on one hand, may favor the EMT of the epithelial cells, and, on the other hand, may reduce the cell response to genotoxic DNA damages. Both consequences can greatly favor cancer onset.
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fig7: Suggested pathway linking chronic inflammation to cancer. In inflamed tissues, such as colon mucosa with UC, a high amount of IL-6 is produced. IL-6 upregulates c-myc protein expression, which, in turn, enhances ribosome biogenesis. The enhanced ribosome biogenesis is responsible for an increased MDM2-mediated p53 degradation. This, on one hand, may favor the EMT of the epithelial cells, and, on the other hand, may reduce the cell response to genotoxic DNA damages. Both consequences can greatly favor cancer onset.

Mentions: In fact, we found that the epithelial cells of patients with UC disease were characterized by a nucleolar hypertrophy, which indicates an upregulated rRNA synthesis,15 a downregulation of p53 expression and a reduction of E-cadherin expression, which is a major phenotypic change indicating the activation of the EMT program.27 The IL-6-induced p53 downregulation mechanism of tumorigenesis in UC is shown schematically in Figure 7, as it may be suggested by the present findings. This mechanism is likely to be functionally active also in other inflammatory foci in which IL-6 is produced and in which IL-6 induces an upregulation of the nucleolar activity, similar to what happens in the epithelial cells of the surface and crypts of human colonic mucosa with UC. Indeed, there is evidence that human hepatocytes in hepatitis virus-related cirrhosis are characterized by a marked nucleolar hypertrophy, and it is worth noting that the number of hepatocytes with nucleolar hypertrophy was directly associated with an increased risk for hepatocellular carcinoma development.32


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)

Suggested pathway linking chronic inflammation to cancer. In inflamed tissues, such as colon mucosa with UC, a high amount of IL-6 is produced. IL-6 upregulates c-myc protein expression, which, in turn, enhances ribosome biogenesis. The enhanced ribosome biogenesis is responsible for an increased MDM2-mediated p53 degradation. This, on one hand, may favor the EMT of the epithelial cells, and, on the other hand, may reduce the cell response to genotoxic DNA damages. Both consequences can greatly favor cancer onset.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: Suggested pathway linking chronic inflammation to cancer. In inflamed tissues, such as colon mucosa with UC, a high amount of IL-6 is produced. IL-6 upregulates c-myc protein expression, which, in turn, enhances ribosome biogenesis. The enhanced ribosome biogenesis is responsible for an increased MDM2-mediated p53 degradation. This, on one hand, may favor the EMT of the epithelial cells, and, on the other hand, may reduce the cell response to genotoxic DNA damages. Both consequences can greatly favor cancer onset.
Mentions: In fact, we found that the epithelial cells of patients with UC disease were characterized by a nucleolar hypertrophy, which indicates an upregulated rRNA synthesis,15 a downregulation of p53 expression and a reduction of E-cadherin expression, which is a major phenotypic change indicating the activation of the EMT program.27 The IL-6-induced p53 downregulation mechanism of tumorigenesis in UC is shown schematically in Figure 7, as it may be suggested by the present findings. This mechanism is likely to be functionally active also in other inflammatory foci in which IL-6 is produced and in which IL-6 induces an upregulation of the nucleolar activity, similar to what happens in the epithelial cells of the surface and crypts of human colonic mucosa with UC. Indeed, there is evidence that human hepatocytes in hepatitis virus-related cirrhosis are characterized by a marked nucleolar hypertrophy, and it is worth noting that the number of hepatocytes with nucleolar hypertrophy was directly associated with an increased risk for hepatocellular carcinoma development.32

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