title: Interleukin 6 downregulates p53 expression and activity by stimulating ribosome biogenesis: a new pathway connecting inflammation to cancer.
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.
authors: Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna, Italy.
authors: E
authors: E
authors: Brighenti
authors: Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy.
authors: C
authors: C
authors: Calabrese
authors: Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy.
authors: G
authors: G
authors: Liguori
authors: 1] Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy [2] Biomedical and Applied Research Center, Azienda Ospedaliero-Universitaria di Bologna, Policlinico S Orsola-Malpighi, Bologna, Italy.
authors: F A
authors: FA
authors: Giannone
authors: Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna, Italy.
authors: D
authors: D
authors: Trerè
authors: Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna, Italy.
authors: L
authors: L
authors: Montanaro
authors: Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna, Italy.
authors: M
authors: M
authors: Derenzini
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012335:RNA, Ribosomal / Q000235:genetics* / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D015820:Cadherins; D015850:Interleukin-6; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012335:RNA, Ribosomal; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2