TGFΒ/SMAD4 Signaling and Altered Epigenetics Contribute to Increased Ovarian Cancer Severity

TGFΒ/SMAD4 Signaling and Altered Epigenetics Contribute to Increased Ovarian Cancer Severity

Bibliographic Details
Main Author: Deatherage, Daniel E.
Language:English
Published: The Ohio State University / OhioLINK 2011
Subjects:
Bioinformatics
Biology
Biomedical Research
Cellular Biology
Molecular Biology
Ovarian Cancer
Epigenetics
DNA hypermethylation
hsa-mir-9-3
Cisplatin resistance
CLDN11
TGF&914
SMAD4
ChIP-sequencing
Survival data
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1306860253
id ndltd-OhioLink-oai-etd.ohiolink.edu-osu1306860253
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Bioinformatics
Biology
Biomedical Research
Cellular Biology
Molecular Biology
Ovarian Cancer
Epigenetics
DNA hypermethylation
hsa-mir-9-3
Cisplatin resistance
CLDN11
TGF&914
SMAD4
ChIP-sequencing
Survival data
spellingShingle Bioinformatics
Biology
Biomedical Research
Cellular Biology
Molecular Biology
Ovarian Cancer
Epigenetics
DNA hypermethylation
hsa-mir-9-3
Cisplatin resistance
CLDN11
TGF&914
SMAD4
ChIP-sequencing
Survival data
Deatherage, Daniel E.
TGFΒ/SMAD4 Signaling and Altered Epigenetics Contribute to Increased Ovarian Cancer Severity
author Deatherage, Daniel E.
author_facet Deatherage, Daniel E.
author_sort Deatherage, Daniel E.
title TGFΒ/SMAD4 Signaling and Altered Epigenetics Contribute to Increased Ovarian Cancer Severity
title_short TGFΒ/SMAD4 Signaling and Altered Epigenetics Contribute to Increased Ovarian Cancer Severity
title_full TGFΒ/SMAD4 Signaling and Altered Epigenetics Contribute to Increased Ovarian Cancer Severity
title_fullStr TGFΒ/SMAD4 Signaling and Altered Epigenetics Contribute to Increased Ovarian Cancer Severity
title_full_unstemmed TGFΒ/SMAD4 Signaling and Altered Epigenetics Contribute to Increased Ovarian Cancer Severity
title_sort tgfβ/smad4 signaling and altered epigenetics contribute to increased ovarian cancer severity
publisher The Ohio State University / OhioLINK
publishDate 2011
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1306860253
work_keys_str_mv AT deatheragedaniele tgfbsmad4signalingandalteredepigeneticscontributetoincreasedovariancancerseverity
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu13068602532021-08-03T06:02:58Z TGFΒ/SMAD4 Signaling and Altered Epigenetics Contribute to Increased Ovarian Cancer Severity Deatherage, Daniel E. Bioinformatics Biology Biomedical Research Cellular Biology Molecular Biology Ovarian Cancer Epigenetics DNA hypermethylation hsa-mir-9-3 Cisplatin resistance CLDN11 TGF&914 SMAD4 ChIP-sequencing Survival data <p>Ovarian cancer is the eighth most common cancer and is the fifth most common cause of cancer related death among women. Early stage ovarian cancer is very responsive to treatments and more than 93% of patients diagnosed with early stage disease achieve a five year survival rate. By contrast less than 30% of patients who are diagnosed with late stage disease achieve a five year survival rate, yet more than 60% of all cases present as late stage. Treatment is typically surgery followed by a chemotherapy regiment of a platinum-based chemotherapeutic and a taxane derivative. While this treatment plan works well for early stage disease, recurrent and late stage cancers are less responsive. Here we present work investigating the altered epigenetics and TGFΒ/SMAD4 signaling pathway in ovarian cancer in an effort to better understand the difference in disease severity at a molecular level. </p><p>We have identified a microRNA hsa-mir-9-3 which is epigenetically repressed by DNA methylation in primary ovarian cancer patients. Quantitative analysis of DNA methylation in the CpG island which contains the hsa-mir-9-3 microRNA revealed significant hypermethylation in both patient samples and cell lines compared to normal tissue. Functional studies reveal that the repression of this microRNA leads to increased proliferation rates and a decrease in apoptosis. We believe that the hypermethylation of the hsa-mir-9-3 locus serves as a novel biomarker for ovarian cancer. </p><p>TGFΒ/SMAD4 signaling is commonly dysregulated in ovarian cancers while being a key growth inhibition signal for the ovarian surface epithelium during menstruation. Here we present a genome-wide profile of SMAD4 binding by ChIP-sequencing following TGFΒ stimulation in the ovarian cancer cell line A2780. We believe this to be the first truly genome-wide profiling of SMAD4 binding using next generation sequencing approaches in an ovarian cancer model. Comparison of ChIP-seq results with previously reported ChIP-chip studies show dramatic biological and technical differences including more than 70% of all SMAD4 binding loci being more than 10kb away from the nearest transcription start site. Gene expression analysis following TGFΒ stimulation revealed a group of 318 genes whose expression changed following SMAD4 binding to the distal promoter of the gene. Of those 318 genes, a subset of them was used to predict patient survival in two independent patient cohorts. These results suggest that the loss of long distance SMAD4 gene regulation following TGFΒ stimulation may play a key role in ovarian carcinogenesis. Additionally, we identified a novel biomarker, CLDN11, whose epigenetic repression is associated increased cisplatin resistance in a tissue culture model system. Examination of CLDN11 expression levels in a previously reported patient cohort revealed lower expression levels associated with increased tumor grade. Finally, loss of CLDN11 expression is associated with increased cellular motility. </p><p>In conclusion we have investigated and correlated several different epigenetic and signaling abnormalities associated with an increase in the severity of ovarian cancer while demonstrating the importance of recent technological advances in genome-wide methodologies. Together these results are likely to aid in both future discovery methods and patient prognosis and treatment.</p> 2011-07-27 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1306860253 http://rave.ohiolink.edu/etdc/view?acc_num=osu1306860253 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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