RESUMEN
An increasing body of evidence connects alterations in the process of alternative splicing with cancer development and progression. However, a direct role of splicing factors as drivers of cancer development is mostly unknown. We analysed the gene copy number of several splicing factors in colon and lung tumours, and found that the gene encoding for the splicing factor SRSF6 is amplified and over-expressed in these cancers. Moreover, over-expression of SRSF6 in immortal lung epithelial cells enhanced proliferation, protected them from chemotherapy-induced cell death and converted them to be tumourigenic in mice. In contrast, knock-down of SRSF6 in lung and colon cancer cell lines inhibited their tumourigenic abilities. SRSF6 up- or down-regulation altered the splicing of several tumour suppressors and oncogenes to generate the oncogenic isoforms and reduce the tumour-suppressive isoforms. Our data suggest that the splicing factor SRSF6 is an oncoprotein that regulates the proliferation and survival of lung and colon cancer cells.
Asunto(s)
Adenocarcinoma/genética , Neoplasias de la Mama/genética , Neoplasias del Colon/genética , Neoplasias Pulmonares/genética , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Fosfoproteínas/genética , Proteínas de Unión al ARN/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Empalme Alternativo , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal/genética , Carcinoma Ductal/metabolismo , Carcinoma Ductal/patología , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Transformación Celular Neoplásica , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas Nucleares/metabolismo , Proteínas Oncogénicas/metabolismo , Fosfoproteínas/metabolismo , Isoformas de Proteínas , Empalme del ARN , Proteínas de Unión al ARN/metabolismo , Factores de Empalme Serina-Arginina , Regulación hacia ArribaRESUMEN
BACKGROUND & AIMS: Acute hepatitis C (AHC) is not frequently identified because patients are usually asymptomatic, although may be recognized after iatrogenic exposures such as needle stick injuries, medical injection, and acupuncture. We describe an outbreak of AHC among 12 patients who received IV saline flush from a single multi-dose vial after intravenous contrast administration for a computerized tomography (CT) scan. The last patient to receive IV contrast with saline flush from a multi-dose vial at the clinic on the previous day was known to have chronic HCV genotype 1b (termed potential source, PS). Here we sought to confirm (via genetic analysis) the source of infection and to predict the minimal contaminating level of IV saline flush needed to transmit infectious virus to all patients. METHODS: In order to confirm the source of infection, we sequenced the HCV E1E2 region in 7 CT patients, in PS, and in 2 control samples from unrelated patients also infected with HCV genotype 1b. A transmission probabilistic model was developed to predict the contamination volume of blood that would have been sufficient to transmit infectious virus to all patients. RESULTS: Viral sequencing showed close clustering of the cases with the PS. The transmission probabilistic model predicted that contamination of the multi-dose saline vial with 0.6-8.7 microliters of blood would have been sufficient to transmit infectious virus to all patients. CONCLUSION: Analysis of this unique cohort provides a new understanding of HCV transmission with respect to contaminating volumes and viral titers.