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Gene expression profile of cervical and skin tissues from human papillomavirus type 16 E6 transgenic mice.

ABSTRACT: Although K14E6 transgenic mice develop spontaneous tumors of the skin epithelium, no spontaneous reproductive tract malignancies arise, unless the transgenic mice were treated chronically with 17beta-estradiol. These findings suggest that E6 performs critical functions in normal adult cervix and skin, highlighting the need to define E6-controlled transcriptional programs in these tissues.We evaluated the expression profile of 14,000 genes in skin or cervix from young K14E6 transgenic mice compared with nontransgenic. To identify differentially expressed genes a linear model was implemented using R and the LIMMA package. Two criteria were used to select the set of relevant genes. First a set of genes with a Log-odds > or = 3 were selected. Then, a hierarchical search of genes was based on Log Fold Changes.Microarray analysis identified a total of 676 and 1154 genes that were significantly up and down-regulated, respectively, in skin from K14E6 transgenic mice. On the other hand, in the cervix from K14E6 transgenic mice we found that only 97 and 252 genes were significantly up and down-regulated, respectively. One of the most affected processes in the skin from K14E6 transgenic mice was the cell cycle. We also found that skin from transgenic mice showed down-regulation of pro-apoptotic genes and genes related to the immune response. In the cervix of K14E6 transgenic mice, we could not find affected any gene related to the cell cycle and apoptosis pathways but did observe alterations in the expression of immune response genes. Pathways such as angiogenesis, cell junction and epidermis development, also were altered in their gene expression profiles in both tissues.Expression of the HPV16 E6 oncoprotein in our model alters expression of genes that fell into several functional groups providing insights into pathways by which E6 deregulate cell cycle progression, apoptosis, the host resistance to infection and immune function, providing new opportunities for early diagnostic markers and therapeutic drug targets.

SUBMITTER: Mendoza-Villanueva D

PROVIDER: S-EPMC2610035 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Gene expression profile of cervical and skin tissues from human papillomavirus type 16 E6 transgenic mice.

Mendoza-Villanueva D D Diaz-Chavez J J Uribe-Figueroa L L Rangel-Escareão C C Hidalgo-Miranda A A March-Mifsut S S Jimenez-Sanchez G G Lambert Pf P Gariglio P P

BMC cancer 20081126

<h4>Background</h4>Although K14E6 transgenic mice develop spontaneous tumors of the skin epithelium, no spontaneous reproductive tract malignancies arise, unless the transgenic mice were treated chronically with 17beta-estradiol. These findings suggest that E6 performs critical functions in normal adult cervix and skin, highlighting the need to define E6-controlled transcriptional programs in these tissues.<h4>Methods</h4>We evaluated the expression profile of 14,000 genes in skin or cervix from ...[more]

PMID: 19036130

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Project description:Background The in vivo properties of HR-HPV E6 and E7 oncoproteins have been previously evaluated through the generation and characterization of HPV transgenic mouse strains. Although K14E6 transgenic mice develop spontaneous tumors of the skin epithelium, no spontaneous reproductive tract malignancies arise, unless the transgenic mice were treated chronically with 17β-estradiol. Taken together, these findings suggest that E6 performs critical functions in normal adult cervix and skin, highlighting the need to define E6-controlled transcriptional programs in these tissues. We evaluated the different expression profile of 14,000 genes in skin or cervix from young K14E6 transgenic mice compared with corresponding tissues from non-transgenic (FVB) mice. Result Microarray analysis identified a total of 676 and 1154 genes that were significantly up and down-regulated, respectively, in skin from K14E6 transgenic mice. On the other hand, in cervix from K14E6 transgenic mice we found that only 97 and 252 genes were significantly up and down-regulated, respectively. One of the most affected processes in the skin from K14E6 transgenic mice was the cell cycle. We also found that skin from transgenic mice showed down-regulation in pro-apoptotic genes expression, particularly in those related to the extrinsic apoptotic pathway. In contrast, we observed up-regulation of anti-apoptotic genes. Another pathway that was severely affected in skin was the immune response. In cervix from transgenic mice, we could not find affected any gene related to the cell cycle and apoptosis pathways. Interestingly, we observed alterations in the expression of immune response genes in cervix from K14E6 transgenic mice. Pathways such as angiogenesis, cell junction, cytoskeleton, keratinocyte differentiation and epidermis development, showed different gene expression in skin or cervix from K14E6 transgenic mice. Conclusion Alterations in gene expression identified in the current study might partially explain why our K14E6 transgenic mice present a more aggressive phenotype in the skin than in the cervix. Expression of the HPV16 E6 oncoprotein alters expression of genes that fell into several functional groups providing insights into pathways by which E6 deregulate cell cycle progression, apoptosis and the host resistance to infection and immune function, providing new opportunities for early diagnostic markers and therapeutic drug targets. Keywords: Human_papillomavirus, transgenic mice, expression profile

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Gene expression profile of cervical and skin tissues from human papillomavirus type 16 E6 transgenic mice.

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Gene expression profile of cervical and skin tissues from human papillomavirus type 16 E6 transgenic mice.

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