ABSTRACT
Ten eleven translocation (TET) enzymes catalyse the oxidative reactions of 5-methylcytosine (5mC) to promote the demethylation process. The reaction intermediate 5-hydroxymethylcytosine (5hmC) has been shown to be abundant in embryonic stem cells and tissues but strongly depleted in human cancers. Genetic mutations of TET2 gene were associated with leukaemia, whereas TET1 downregulation has been shown to promote malignancy in breast cancer. Here we report that TET1 is downregulated in colon tumours from the initial stage. TET1 silencing in primary epithelial colon cells increase their cellular proliferation while its re-expression in colon cancer cells inhibits their proliferation and the growth of tumour xenografts even at later stages. We found that TET1 binds to the promoter of the DKK gene inhibitors of the WNT signalling to maintain them hypomethylated. Downregulation of TET1 during colon cancer initiation leads to repression, by DNA methylation, the promoters of the inhibitors of the WNT pathway resulting in a constitutive activation of the WNT pathway. Thus the DNA hydroxymethylation mediated by TET1 controlling the WNT signalling is a key player of tumour growth. These results provide new insights for understanding how tumours escape cellular controls.
Subject(s)
Colonic Neoplasms/genetics , DNA-Binding Proteins/genetics , Proto-Oncogene Proteins/genetics , Tumor Suppressor Proteins/genetics , Wnt Signaling Pathway/genetics , Animals , Antibiotics, Antineoplastic/pharmacology , Blotting, Western , Caco-2 Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , DNA Methylation/drug effects , DNA Methylation/genetics , DNA-Binding Proteins/metabolism , Doxorubicin/pharmacology , Flow Cytometry , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Mixed Function Oxygenases , Proto-Oncogene Proteins/metabolism , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Tumor Burden/drug effects , Tumor Burden/genetics , Tumor Suppressor Proteins/metabolism , Wnt Signaling Pathway/drug effects , Xenograft Model Antitumor AssaysABSTRACT
This study consists in the reconnaissance of the carcinogenic risk in some processing in Ferrara. The main object is to know, to estimate and to verify the diffusion of the carcinogenic substances and to estimate the number of the exposed or potentially exposed workers. The study has interested the synthesis chemistry and polymer production, woodworking, welding on stainless steel and chromium conversion coating and chrome electroplating. The research has involved 54 factories and 436 workers estimated exposed or potentially exposed to carcinogenic substances. The survey has consisted of inspections in the working places, collection of exposure data, control of the precautionary measures and exposure determination in the case of stainless steel welding. The smallest factories had less knowledge of the risk and for this reason it is necessary to keep constant attention.
Subject(s)
Carcinogens, Environmental/adverse effects , Chemical Industry , Chromium/adverse effects , Dust , Electroplating , Health Surveys , Humans , Italy , Neoplasms/etiology , Nickel/adverse effects , Occupational Exposure/adverse effects , Polymers/adverse effects , Risk Factors , Stainless Steel/adverse effects , Time Factors , Welding , Wood/adverse effectsABSTRACT
The preoperative diagnosis of carcinoma of the gallbladder is very difficult because the clinical manifestations of this disease are nonspecific and often indistinguishable from those of cholecystitis. Radiography, including oral cholecystograms and i.v. cholangiograms, give aspecific findings. Ultrasound scans were performed on 13 gallbladder carcinomas: only "massive" cancer was diagnosed correctly, because sonography does not offer specific patterns for "infiltrating" and "fungating" carcinomas.
