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Up regulation in gene expression of chromatin remodelling factors in cervical intraepithelial neoplasia.

Shadeo A, Chari R, Lonergan KM, Pusic A, Miller D, Ehlen T, Van Niekerk D, Matisic J, Richards-Kortum R, Follen M, Guillaud M, Lam WL, MacAulay C - BMC Genomics (2008)

Bottom Line: Frontline monitoring has reduced these rates in developed countries and present day screening programs primarily identify precancerous lesions termed cervical intraepithelial neoplasias (CIN).Our results indicate deregulation of the chromatin remodelling complex components and its influencing factors occur in the development of CIN lesions.The increase in SWI/SNF stabilizing molecule SMARCC1 and other novel genes has not been previously illustrated as events in the early stages of dysplasia development and thus not only provides novel candidate markers for screening but a biological function for targeting treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Genetics & Developmental Biology, British Columbia Cancer Research Centre, Vancouver, BC, Canada. ashadeo@bccrc.ca.

ABSTRACT

Background: The highest rates of cervical cancer are found in developing countries. Frontline monitoring has reduced these rates in developed countries and present day screening programs primarily identify precancerous lesions termed cervical intraepithelial neoplasias (CIN). CIN lesions described as mild dysplasia (CIN I) are likely to spontaneously regress while CIN III lesions (severe dysplasia) are likely to progress if untreated. Thoughtful consideration of gene expression changes paralleling the progressive pre invasive neoplastic development will yield insight into the key casual events involved in cervical cancer development.

Results: In this study, we have identified gene expression changes across 16 cervical cases (CIN I, CIN II, CIN III and normal cervical epithelium) using the unbiased long serial analysis of gene expression (L-SAGE) method. The 16 L-SAGE libraries were sequenced to the level of 2,481,387 tags, creating the largest SAGE data collection for cervical tissue worldwide. We have identified 222 genes differentially expressed between normal cervical tissue and CIN III. Many of these genes influence biological functions characteristic of cancer, such as cell death, cell growth/proliferation and cellular movement. Evaluation of these genes through network interactions identified multiple candidates that influence regulation of cellular transcription through chromatin remodelling (SMARCC1, NCOR1, MRFAP1 and MORF4L2). Further, these expression events are focused at the critical junction in disease development of moderate dysplasia (CIN II) indicating a role for chromatin remodelling as part of cervical cancer development.

Conclusion: We have created a valuable publically available resource for the study of gene expression in precancerous cervical lesions. Our results indicate deregulation of the chromatin remodelling complex components and its influencing factors occur in the development of CIN lesions. The increase in SWI/SNF stabilizing molecule SMARCC1 and other novel genes has not been previously illustrated as events in the early stages of dysplasia development and thus not only provides novel candidate markers for screening but a biological function for targeting treatment.

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Biological functions targeted by gene expression changes between NC and CIN III Functional categories deemed as significant by Ingenuity Pathway Analysis software, are displayed along the x-axis. The y-axis displays the -(log) significance and the orange horizontal line denotes the cut off for significance (p-value of 0.05). The functional categories most significantly influenced include cell death, cell growth and proliferation and cell movement.
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Figure 3: Biological functions targeted by gene expression changes between NC and CIN III Functional categories deemed as significant by Ingenuity Pathway Analysis software, are displayed along the x-axis. The y-axis displays the -(log) significance and the orange horizontal line denotes the cut off for significance (p-value of 0.05). The functional categories most significantly influenced include cell death, cell growth and proliferation and cell movement.

Mentions: The mean score of tags in the four NC libraries were compared to the mean score of tags in the six severe neoplasia libraries (CIN III). We identified 108 tags increased in frequency in CIN III and 138 tags decreased and overall observed 246 tags differentially expressed between NC tissue and CIN III [see Additional file 5]. Two hundred and forty tags mapped to 222 unique genes. Genes differentially expressed between normal and CIN III were evaluated for gene network associations using Ingenuity Pathway Analysis [11]. Biological functions most influenced by these genes include cell death, cell growth/proliferation and cellular movement (Figure 3). The gene network with the most number of differentially expressed genes influenced cellular processes such as cell cycle and cell morphology and involved 17 of the differentially expressed genes (Table 1, Figure 4). The network with the higher magnitude gene expression changes influenced cell cycle and gene expression (Figure 5).


Up regulation in gene expression of chromatin remodelling factors in cervical intraepithelial neoplasia.

Shadeo A, Chari R, Lonergan KM, Pusic A, Miller D, Ehlen T, Van Niekerk D, Matisic J, Richards-Kortum R, Follen M, Guillaud M, Lam WL, MacAulay C - BMC Genomics (2008)

Biological functions targeted by gene expression changes between NC and CIN III Functional categories deemed as significant by Ingenuity Pathway Analysis software, are displayed along the x-axis. The y-axis displays the -(log) significance and the orange horizontal line denotes the cut off for significance (p-value of 0.05). The functional categories most significantly influenced include cell death, cell growth and proliferation and cell movement.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2277413&req=5

Figure 3: Biological functions targeted by gene expression changes between NC and CIN III Functional categories deemed as significant by Ingenuity Pathway Analysis software, are displayed along the x-axis. The y-axis displays the -(log) significance and the orange horizontal line denotes the cut off for significance (p-value of 0.05). The functional categories most significantly influenced include cell death, cell growth and proliferation and cell movement.
Mentions: The mean score of tags in the four NC libraries were compared to the mean score of tags in the six severe neoplasia libraries (CIN III). We identified 108 tags increased in frequency in CIN III and 138 tags decreased and overall observed 246 tags differentially expressed between NC tissue and CIN III [see Additional file 5]. Two hundred and forty tags mapped to 222 unique genes. Genes differentially expressed between normal and CIN III were evaluated for gene network associations using Ingenuity Pathway Analysis [11]. Biological functions most influenced by these genes include cell death, cell growth/proliferation and cellular movement (Figure 3). The gene network with the most number of differentially expressed genes influenced cellular processes such as cell cycle and cell morphology and involved 17 of the differentially expressed genes (Table 1, Figure 4). The network with the higher magnitude gene expression changes influenced cell cycle and gene expression (Figure 5).

Bottom Line: Frontline monitoring has reduced these rates in developed countries and present day screening programs primarily identify precancerous lesions termed cervical intraepithelial neoplasias (CIN).Our results indicate deregulation of the chromatin remodelling complex components and its influencing factors occur in the development of CIN lesions.The increase in SWI/SNF stabilizing molecule SMARCC1 and other novel genes has not been previously illustrated as events in the early stages of dysplasia development and thus not only provides novel candidate markers for screening but a biological function for targeting treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Genetics & Developmental Biology, British Columbia Cancer Research Centre, Vancouver, BC, Canada. ashadeo@bccrc.ca.

ABSTRACT

Background: The highest rates of cervical cancer are found in developing countries. Frontline monitoring has reduced these rates in developed countries and present day screening programs primarily identify precancerous lesions termed cervical intraepithelial neoplasias (CIN). CIN lesions described as mild dysplasia (CIN I) are likely to spontaneously regress while CIN III lesions (severe dysplasia) are likely to progress if untreated. Thoughtful consideration of gene expression changes paralleling the progressive pre invasive neoplastic development will yield insight into the key casual events involved in cervical cancer development.

Results: In this study, we have identified gene expression changes across 16 cervical cases (CIN I, CIN II, CIN III and normal cervical epithelium) using the unbiased long serial analysis of gene expression (L-SAGE) method. The 16 L-SAGE libraries were sequenced to the level of 2,481,387 tags, creating the largest SAGE data collection for cervical tissue worldwide. We have identified 222 genes differentially expressed between normal cervical tissue and CIN III. Many of these genes influence biological functions characteristic of cancer, such as cell death, cell growth/proliferation and cellular movement. Evaluation of these genes through network interactions identified multiple candidates that influence regulation of cellular transcription through chromatin remodelling (SMARCC1, NCOR1, MRFAP1 and MORF4L2). Further, these expression events are focused at the critical junction in disease development of moderate dysplasia (CIN II) indicating a role for chromatin remodelling as part of cervical cancer development.

Conclusion: We have created a valuable publically available resource for the study of gene expression in precancerous cervical lesions. Our results indicate deregulation of the chromatin remodelling complex components and its influencing factors occur in the development of CIN lesions. The increase in SWI/SNF stabilizing molecule SMARCC1 and other novel genes has not been previously illustrated as events in the early stages of dysplasia development and thus not only provides novel candidate markers for screening but a biological function for targeting treatment.

Show MeSH
Related in: MedlinePlus