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

• Published in: Oncogene Vol. 33; no. 35; pp. 4396 - 4406
• Main Authors: Brighenti, E, Calabrese, C, Liguori, G, Giannone, F A, Trerè, D, Montanaro, L, Derenzini, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.08.2014; Nature Publishing Group
• Subjects: 631/67/581; 631/80/86; 692/420/256/2515; 692/699/67; Adult; Anti-Inflammatory Agents - therapeutic use; Apoptosis; Biosynthesis; Cadherins - metabolism; Cancer; Carcinogenesis; Cell Biology; Cell Line, Tumor; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Development and progression; Epithelial-Mesenchymal Transition - drug effects; Female; Gene Expression Regulation - drug effects; Genetic aspects; Hep G2 Cells; Human Genetics; Humans; Inflammation; Inflammatory diseases; Interleukin-6; Interleukin-6 - pharmacology; Internal Medicine; Male; Medicine; Medicine & Public Health; Middle Aged; Oncology; Original; original-article; Properties; Proto-Oncogene Proteins c-mdm2 - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Ribonucleic acid; Ribosomal Proteins - metabolism; Ribosomes - genetics; Ribosomes - metabolism; RNA; RNA, Ribosomal - genetics; RNA, Ribosomal - metabolism; Signal Transduction; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; cancer; EMT; IL-6; chronic inflammation; ribosome biogenesis; p53
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.1

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.