Modulación de la expresión de los ncmtRNAs por la proteína HBx-HBV
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Fecha
2015
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es
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Universidad Andrés Bello
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Licencia CC
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Resumen
El carcinoma hepatocelular (CHC) es la tercera causa de muerte por cáncer a nivel mundial.
La Infección crónica con Virus de la Hepatitis B (HBV) es el principal factor de riesgo para
el desarrollo de CHC. Actualmente, se ha relacionado a la proteína X de HBV (HBx) en la
patogénesis de CHC inducida por HBV. Sin embargo, el mecanismo molecular implicado
en el desarrollo de CHC, aún es pobremente entendido. A pesar de la gran variedad de
tratamientos anti-tumorales como antivirales existente, la alta tasa refractaria de estos han
hecho que la búsqueda de una terapia contra el cáncer hepático, independiente del factor de
riesgo, sea el mayor desafió actual. Nuestro grupo ha reportado la expresión diferencial de
una familia de RNAs no codificantes de origen mitocondrial (ncmtRNA) entre células
normales y tumorales. Células normales en proliferación expresan dos transcritos; sentido
(SncmtRNA) y antisentido (ASncmtRNA). En contraste, células tumorales expresan el
SncmtRNA, pero regulan negativamente la expresión de los antisentidos. Interferencia de
los ASncmtRNAs en líneas derivadas de CHC, induce masiva muerte celular por apóptosis
y una disminución del potencial tumorigénico, lo cual no se observa en células normales.
Por otro lado, se observó que células tumorales así como el cultivo primario hepático
murino que expresan la proteína HBx, desregulan la expresión de los ncmtRNAs más aún,
se observa la expresión de un segundo transcrito sentido (SncmtRNA-2), al cual se ha
asociado a procesos de inmortalización celular. Esto sugiere que el uso de ASOs dirigidos a
los ASncmtRNAs puede ser una nueva herramienta terapéutica eficaz y selectiva contra el
cáncer Hepático.
Hepatocellular Carcinoma (HCC) is the third leading cause of cancer death worldwide. Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of HCC. Current reports have linked the HBV X protein (HBx) in the pathogenesis of HBVinduced HCC. However, the molecular mechanism involved in the development of HCC, are still poorly understood. Despite the variety of anti-tumor treatments such as antiviral available today, the low rate of success of such have made the search for an ideal therapy for liver cancer become one of the biggest challenges nowadays. Our group has described a family of non-coding RNAs of mitochondrial origin (ncmtRNAs) exhibiting differential expression profile according to the proliferative state. Normal proliferating cells express two transcripts; sense (SncmtRNA) and antisense (ASncmtRNA). While tumor cells express SncmtRNA but negatively regulate the expression of antisense. Treatment with oligonucleotides (ASOs) in cell lines derived from HCC, induced massive apoptotic death and decreased tumorigenic potential, which was not observed in normal cells. Moreover, tumor cells and murine liver primary cultures overexpressing the HBx protein have a deregulated expression of these ncmtRNAs. In adition, the expression of a second transcribed sense (SncmtRNA-2) was observed, which has been associated to cell immortalization. This study suggests that the use of ASOs that target ASncmtRNAs may be a new efficient therapeutic tool to target Liver cancer.
Hepatocellular Carcinoma (HCC) is the third leading cause of cancer death worldwide. Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of HCC. Current reports have linked the HBV X protein (HBx) in the pathogenesis of HBVinduced HCC. However, the molecular mechanism involved in the development of HCC, are still poorly understood. Despite the variety of anti-tumor treatments such as antiviral available today, the low rate of success of such have made the search for an ideal therapy for liver cancer become one of the biggest challenges nowadays. Our group has described a family of non-coding RNAs of mitochondrial origin (ncmtRNAs) exhibiting differential expression profile according to the proliferative state. Normal proliferating cells express two transcripts; sense (SncmtRNA) and antisense (ASncmtRNA). While tumor cells express SncmtRNA but negatively regulate the expression of antisense. Treatment with oligonucleotides (ASOs) in cell lines derived from HCC, induced massive apoptotic death and decreased tumorigenic potential, which was not observed in normal cells. Moreover, tumor cells and murine liver primary cultures overexpressing the HBx protein have a deregulated expression of these ncmtRNAs. In adition, the expression of a second transcribed sense (SncmtRNA-2) was observed, which has been associated to cell immortalization. This study suggests that the use of ASOs that target ASncmtRNAs may be a new efficient therapeutic tool to target Liver cancer.
Notas
Tesis (Bioquímico, Magíster en Bioquímica)
Palabras clave
Carcinoma Hepatocelular, Proteínas, ARN