RESUMO
TBX15 is a T-box transcription factor essential for development, also proposed as a marker in prostate cancer; and, recently, its antiapoptotic function indicates a role in carcinogenesis. Regulation of TBX15 is uncovered. In this study, we investigated the regulation of TBX15 expression in human cancer cells, by analyzing the regulatory function of a 5'-distal conserved region of TBX15. Bisulfite sequencing showed high methylation of the CpG island contained in this region that was not correlated with TBX15 mRNA levels, in the cancer cell lines analyzed; however, after 5-aza-dC treatment of TPC-1 cells an increase of TBX15 expression was observed. We also found a significant response of TBX15 to TNF-α activation of the NF-κB pathway using five cancer cell lines, and similar results were obtained when NF-κB was activated with PMA/ionomycin. Next, by luciferase reporter assays, we identified the TBX15 regulatory region containing two functional NF-κB binding sites with response to NF-κBp65, mapping on the -3302 and -3059 positions of the TBX15 gene. Moreover, a direct interaction of NF-κBp65 with one of the two NF-κB binding sites was indicated by ChIP assays. In summary, we provide novel data showing that NF-κB signaling up-regulates TBX15 expression in cancer cells. Furthermore, the link between TBX15 and NF-κB found in this study may be important to understand cancer and development processes.
Assuntos
Regulação Neoplásica da Expressão Gênica , NF-kappa B/metabolismo , Neoplasias/genética , Proteínas com Domínio T/genética , Região 5'-Flanqueadora/genética , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Imunoprecipitação da Cromatina , Sequência Conservada/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias/patologia , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Proteínas com Domínio T/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Tumor necrosis factor (TNF) inhibitors are widely used for the treatment of various rheumatic diseases. These agents may lead to development of systemic autoimmune diseases and renal complications. We report a patient with psoriatic arthritis and renal failure treated with two TNF inhibitors (Etanercept and then Adalimumab). After this treatment he developed proteinuria with nephrotic syndrome. A renal biopsy was performed highlighting GN with mesangial IgA deposits. Then he developed p-ANCA positivity. Following that, etanercept and adalimumab were stopped and a treatment by corticosteroids was initiated, but renal function decreased. Currently the patient is treated by haemodialysis. In our patient, the pathogenic role for anti-TNF therapy is suggested by the close temporal relationship with development of glomerular disease and by the improvement in proteinuria after drug withdrawal. However, the patient was treated once more with TNF agents, so he developed end stage renal disease.