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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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Summary of validation panel quantitative PCR results of genes with altered expression in CIN III L-SAGE libraries. A panel of 22 new cases was investigated in triplicate for expression changes for eight genes. Samples are indicated as follows: CIN I (A-C), CIN I/II (D), CIN II (E-J), CIN III (K-Q) and tumour (R). Zero on the Y-axis denotes mean expression levels of the respective genes in three NC cervical tissues. Expression in tumour is relative to matched normal.
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Figure 6: Summary of validation panel quantitative PCR results of genes with altered expression in CIN III L-SAGE libraries. A panel of 22 new cases was investigated in triplicate for expression changes for eight genes. Samples are indicated as follows: CIN I (A-C), CIN I/II (D), CIN II (E-J), CIN III (K-Q) and tumour (R). Zero on the Y-axis denotes mean expression levels of the respective genes in three NC cervical tissues. Expression in tumour is relative to matched normal.

Mentions: The validation panel consists of 22 samples representing NC, CIN I, CIN II and CIN III in addition to a tumor sample with paired normal tissue. Quantitative analysis of expression was determined for each gene on this panel by real-time PCR using TaqMan® Gene Expression Assays (Figure 6). NCOR1 expression increased in nine of ten CIN I/II samples ranging from 1.3–6.0 fold increase relative to NC with a statistically significant overall all trend (p < 0.05). SMARCC1 expression increase was confirmed in six CIN I/II samples and four CIN III cases (Figure 6). Similarly, we confirmed the increased expression of DHFR and MRFAP1 in the validation panel including in nine of ten CIN I/II cases and six of seven CIN III cases and the overall trend of increase for this gene was statistically significant (p < .05). MORF4L2 expression increase was confirmed in eight of ten CIN I/II and six of seven CIN III with statistically significant overall trend of increase (p < .05) in the validation panel. Although we were able to confirm decreased CDKN2B expression in the tumour, we were unable to confirm this in the earlier staged cases in the validation panel. Reduced expression of phosphatase and tensin homolog (PTEN) was confirmed in two CIN II and two CIN III cases [see Additional file 6].


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)

Summary of validation panel quantitative PCR results of genes with altered expression in CIN III L-SAGE libraries. A panel of 22 new cases was investigated in triplicate for expression changes for eight genes. Samples are indicated as follows: CIN I (A-C), CIN I/II (D), CIN II (E-J), CIN III (K-Q) and tumour (R). Zero on the Y-axis denotes mean expression levels of the respective genes in three NC cervical tissues. Expression in tumour is relative to matched normal.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Summary of validation panel quantitative PCR results of genes with altered expression in CIN III L-SAGE libraries. A panel of 22 new cases was investigated in triplicate for expression changes for eight genes. Samples are indicated as follows: CIN I (A-C), CIN I/II (D), CIN II (E-J), CIN III (K-Q) and tumour (R). Zero on the Y-axis denotes mean expression levels of the respective genes in three NC cervical tissues. Expression in tumour is relative to matched normal.
Mentions: The validation panel consists of 22 samples representing NC, CIN I, CIN II and CIN III in addition to a tumor sample with paired normal tissue. Quantitative analysis of expression was determined for each gene on this panel by real-time PCR using TaqMan® Gene Expression Assays (Figure 6). NCOR1 expression increased in nine of ten CIN I/II samples ranging from 1.3–6.0 fold increase relative to NC with a statistically significant overall all trend (p < 0.05). SMARCC1 expression increase was confirmed in six CIN I/II samples and four CIN III cases (Figure 6). Similarly, we confirmed the increased expression of DHFR and MRFAP1 in the validation panel including in nine of ten CIN I/II cases and six of seven CIN III cases and the overall trend of increase for this gene was statistically significant (p < .05). MORF4L2 expression increase was confirmed in eight of ten CIN I/II and six of seven CIN III with statistically significant overall trend of increase (p < .05) in the validation panel. Although we were able to confirm decreased CDKN2B expression in the tumour, we were unable to confirm this in the earlier staged cases in the validation panel. Reduced expression of phosphatase and tensin homolog (PTEN) was confirmed in two CIN II and two CIN III cases [see Additional file 6].

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