Expresión del RNA mitocondrial no codificante sentido 2 (SncmtRNA-2) durante la transformación celular asociado a infección del virus del papiloma humano (HPV)
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2013
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es
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Universidad Andrés Bello
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Resumen
El 99% de los casos de cáncer cervicouterino está dado por infecciones
persistentes con el Virus del Papiloma Humano (HPV). Hemos reportado previamente una
familia de RNAs mitocondriales no codificantes (ncmtRNAs) que son expresados
diferencialmente de acuerdo al tipo celular. Células normales en proliferación expresan un
transcrito sentido (SncmtRNA-1) y dos transcritos antisentido (ASncmtRNA-1 y 2). Por
otra parte, células tumorales expresan el SncmtRNA-1 pero reprimen la expresión de los
ASncmtRNAs. Utilizando la infección por HPV como un modelo de transformación
celular, encontramos que queratinocitos inmortalizados con HPV-16/18 expresan un nuevo
transcrito sentido denominado SncmtRNA-2, el cual se expresa en muy bajos niveles en
células normales o transformadas por HPV.
En el presente trabajo, hipotetizamos que el proceso de inmortalizacióntransformación celular depende de los niveles de expresión del SncmtRNA-2. Para probar
esta hipótesis, células inmortalizadas con HPV-16/18 fueron transducidas con un vector
lentiviral que codifica para ras para inducir la transformación celular definitiva. La sobreexpresión de RAS indujo características tumorales en células inmortalizadas con HPV-18,
tales como una mayor tasa de proliferación, capacidad de migración-invasión y propiedades
clonogénicas. Aún más, las células inmortalizadas con HPV-18 que sobre-expresan RAS
bajaron la expresión del SncmtRNA-2, tal como previamente fue observado en HeLa, Silla
y Caski (células transformadas por HPV). Por otro lado, células inmortalizadas con HPV16 que sobre-expresan RAS mostraron una alta tasa proliferativa y una moderada capacidad
de migración, pero no adquirieron propiedades clonogénicas. Interesantemente, estas
células no reprimieron la expresión del SncmtRNA-2. Los resultados descritos aquí
sugieren fuertemente que el SncmtRNA-2 podría estar implicado en mantener el estadio
pre-tumoral, aunque se requieren futuros estudios para comprender completamente la
función de estas moléculas.
The 99% of cervical cancer cases is given by persistent infection with the Human Papillomavirus (HPV). We previously reported a family of on coding mitochondria) RNAs (ncmtRNAs) which are differentially expressed according to the cell type. Normal cells in proliferation express a sense transcript named SncmtRNA-1 and two antisense transcripts named ASncmtRNA-1 and 2. On the other hand, tumor cells express the SncmtRNA-1 but down-regulate the ASncmtRNAs. Using the HPV infection as a cellular transformation model, we found that HPV-16/18 immortalized keratinocytes express a new sense transcript named SncmtRNA-2, which is poorly expressed in normal cells or HPVtransformed cells. In the present work, we hypothesized that the process of immortalizationtransformation of cells is dependent on the expression levels of the SncmtRNA-2. In order to test this hypothesis, HPV-16/18 immortalized cells were transduced with lentiviral vectors coding for ras to induce definitive cell transformation. The over-expression of RAS induced tumor features in HPV-18 immortalized cells, such as a higher proliferating rate, migration-invasion capacity and clonogenic properties. Furthermore, HPV-18 immortalized cells over-expressing RAS showed a down-regulation of the SncmtRNA-2, as previously observed in Hela, SiHa and Caski (HPV transformed cells). By other hand, HPV-16 immortalized cells over-expressing RAS showed higher proliferating rates and a mild migration capacity but did not aquire clonogenic properties. Interestingly, these cells did not down regulate the expression of the SncmtRNA-2. The results described here strongly suggest that the SncmtRNA-2 would be involved in maintaining the pre-tumoral stage, although future studies are necessary to fully understand the function of this molecule.
The 99% of cervical cancer cases is given by persistent infection with the Human Papillomavirus (HPV). We previously reported a family of on coding mitochondria) RNAs (ncmtRNAs) which are differentially expressed according to the cell type. Normal cells in proliferation express a sense transcript named SncmtRNA-1 and two antisense transcripts named ASncmtRNA-1 and 2. On the other hand, tumor cells express the SncmtRNA-1 but down-regulate the ASncmtRNAs. Using the HPV infection as a cellular transformation model, we found that HPV-16/18 immortalized keratinocytes express a new sense transcript named SncmtRNA-2, which is poorly expressed in normal cells or HPVtransformed cells. In the present work, we hypothesized that the process of immortalizationtransformation of cells is dependent on the expression levels of the SncmtRNA-2. In order to test this hypothesis, HPV-16/18 immortalized cells were transduced with lentiviral vectors coding for ras to induce definitive cell transformation. The over-expression of RAS induced tumor features in HPV-18 immortalized cells, such as a higher proliferating rate, migration-invasion capacity and clonogenic properties. Furthermore, HPV-18 immortalized cells over-expressing RAS showed a down-regulation of the SncmtRNA-2, as previously observed in Hela, SiHa and Caski (HPV transformed cells). By other hand, HPV-16 immortalized cells over-expressing RAS showed higher proliferating rates and a mild migration capacity but did not aquire clonogenic properties. Interestingly, these cells did not down regulate the expression of the SncmtRNA-2. The results described here strongly suggest that the SncmtRNA-2 would be involved in maintaining the pre-tumoral stage, although future studies are necessary to fully understand the function of this molecule.
Notas
Tesis (Bioquímico, Magíster en Bioquímica)
Esta Tesis fue financiada por el proyecto FONDECYT N°11090060: "Determination of the expression of non-coding mitochondrial RNAs during cell transformation induced by human papillomavirus type 16 and early detection of cervical cancer".
Esta Tesis fue financiada por el proyecto FONDECYT N°11090060: "Determination of the expression of non-coding mitochondrial RNAs during cell transformation induced by human papillomavirus type 16 and early detection of cervical cancer".
Palabras clave
Papillomavirus, ADN Mitocondrial