RESUMO
It is acknowledged that nonsteroidal anti-inflammatory drugs (NSAIDs) can participate in various signaling pathways, while information about their epigenetic effects are limited. p75NTR (p75 neurotrophin receptor) can inhibit tumor growth by inducing cell cycle arrest and regulating cell cycle arrest and apoptotic cell death. The expression of p75NTR is influenced by epigenetic roles. We explored the effects of ibuprofen on p75NTR expression and investigated whether promoter methylation and N6-methyladenosine (m6A) RNA methylation regulates this process in human gastric cancer cells (SGC7901 and MKN45). Cell lines were treated with ibuprofen 0, 2.5, 5, 10, 20 µM, and then DNA, RNA, and protein were isolated 24 h later. Expression and promoter methylation of p75NTR were detected by RT-qPCR and Western blot. The levels of m6A-p75NTR were measured by RNA immunoprecipitation. We also used RT-qPCR to determine the levels of m6A-related regulators, METTL3, METTL14, ALKBH5, FTO, YTHDC2, and YTHDF1-3. Ibuprofen attenuated p75NTR promoter methylation (p < 0.01) and increased p75NTR level (p < 0.001). Ibuprofen increased m6A-p53 expression (p < 0.01) by promoting the expression of METTL3 (p < 0.01) and METTL14 (p < 0.05); and increased levels of YTHDF1 (p < 0.001), YTHDF3 (p < 0.001), and YTHDC2 (p < 0.01) that finally reinforced p53 translation (p < 0.01). Therefore, our results present that ibuprofen epigenetically increased p75NTR expression by downregulating promoter methylation and upregulating m6A-RNA-methylation in SGC7901 and MKN45 cells. Our study unveils a novel mechanism for p75NTR regulation by NSAIDs and helps the design of treatment targets.
Assuntos
Adenosina , Metilação de DNA , Ibuprofeno , Metiltransferases , Proteínas do Tecido Nervoso , Receptores de Fator de Crescimento Neural , Neoplasias Gástricas , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacologia , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Metilação de DNA/efeitos dos fármacos , Humanos , Ibuprofeno/farmacologia , Metiltransferases/genética , Metiltransferases/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA/genética , RNA/metabolismo , RNA Mensageiro/genética , Receptor de Fator de Crescimento Neural/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
Blue rubber bleb nevus syndrome (BRBNS) is a rare syndrome characterized by multiple vascular malformations of varying size and appearance that present predominantly on the skin and within the gastrointestinal tract and, less often, in other internal organs. Gastrointestinal lesions of BRBNS can cause acute or chronic bleeding, and the treatment is challenging. In this case, we reported a successful treatment of vascular malformations in all segments of gastrointestinal tract, including the small intestine, by endoscopic sclerotherapy, in a 10-year-old boy with BRBNS.