ABSTRACT
This study was designed to evaluate MEK5 and ERK5 expression in colon cancer progression and to ascertain the relevance of MEK5/ERK5 signalling in colon cancer. Expression of MEK5 and ERK5 was evaluated in 323 human colon cancer samples. To evaluate the role of MEK5/ERK5 signalling in colon cancer, we developed a stable cell line model with differential MEK5/ERK5 activation. Impact of differential MEK5/ERK5 signalling was evaluated on cell cycle progression by flow cytometry and cell migration was evaluated by wound healing and transwell migration assays. Finally, we used an orthotopic xenograft mouse model of colon cancer to assess tumour growth and progression. Our results demonstrated that MEK5 and ERK5 are overexpressed in human adenomas (P<0.01) and adenocarcinomas (P<0.05), where increased ERK5 expression correlated with the acquisition of more invasive and metastatic potential (P<0.05). Interestingly, we observed a significant correlation between ERK5 expression and NF-κB activation in human adenocarcinomas (P<0.001). We also showed that ERK5 overactivation significantly accelerated cell cycle progression (P<0.05) and increased cell migration (P<0.01). Furthermore, cells with overactivated ERK5 displayed increased NF-κB nuclear translocation and transcriptional activity (P<0.05), together with increased expression of the mesenchymal marker vimentin (P<0.05). We further demonstrated that increased NF-κB activation was associated with increased IκB phosphorylation and degradation (P<0.05). Finally, in the mouse model, lymph node metastasis was exclusively seen in orthotopically implanted tumours with overactivated MEK5/ERK5, and not in tumours with inhibited MEK5/ERK5. Our results suggested that MEK5/ERK5/NF-κB signalling pathway is important for tumour onset, progression and metastasis, possibly representing a novel relevant therapeutic target in colon cancer treatment.
Subject(s)
Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , MAP Kinase Signaling System , Mitogen-Activated Protein Kinase 7/metabolism , NF-kappa B/metabolism , Adult , Aged , Aged, 80 and over , Animals , Cell Movement/physiology , Colonic Neoplasms/enzymology , Colonic Neoplasms/pathology , Disease Progression , Female , Humans , Male , Mice , Middle Aged , Phosphorylation , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
The familial form of myasthenia gravis is a relatively rare condition, occurring in about 3.4 per cent of myasthenic patients. Two familial cases with ocular myasthenia gravis are reported. They had a third brother who died probably with the same disease. Their parents are cousins. The authors made a brief approach of genetic, clinical, statistical and therapeutic aspects of the disease.
Subject(s)
Myasthenia Gravis/genetics , Adult , Cholinesterase Inhibitors/therapeutic use , Consanguinity , Female , Humans , Male , Myasthenia Gravis/pathology , Myasthenia Gravis/therapy , Thymectomy , Thymus Gland/pathologyABSTRACT
Os autores realizam levantamento dos enfermos com heredodegeneracao cerebelomedular, acompanhados no Servico de Neurologia da Faculdade de Medicina da Universidade Federal Fluminense, nos ultimos 15 anos, estudando seus aspectos peculiares, suas distintas formas de apresentacao e as associacoes observadas com certas enfermidades sistemicas, especialmente com aquelas do aparelho cardiovascular. Comparam os achados de sua causistica com aqueles da literatura
