Aberrant Promoter Methylation of Sparc in Ovarian Cancer
Epigenetic silencing of tumor suppressor genes is a new focus of investigation in the generation and proliferation of carcinomas. Secreted protein acidic and rich in cysteine (SPARC) is reportedly detrimental to the growth of ovarian cancer cells and has been shown to be epigenetically silenced in...
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Elsevier
2009-02-01
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Series: | Neoplasia: An International Journal for Oncology Research |
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doaj-4ec7828989774802bac69cfa400d25042020-11-24T22:17:14ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022009-02-0111212613510.1593/neo.81146Aberrant Promoter Methylation of Sparc in Ovarian CancerMatthew J. Socha0Neveen Said1Yanshan Dai2Joseph Kwong3Preetha Ramalingam4Vuong Trieu5Neil Desai6Samuel C. Mok7Kouros Motamed8Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912, USAVascular Biology Center, Medical College of Georgia, Augusta, GA 30912, USAAbraxis BioScience LLC, Marina del Rey, CA 90292, USALaboratory of Gynecologic Oncology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Pathology, Medical College of Georgia, Augusta, GA 30912, USAAbraxis BioScience LLC, Marina del Rey, CA 90292, USAAbraxis BioScience LLC, Marina del Rey, CA 90292, USALaboratory of Gynecologic Oncology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USAVascular Biology Center, Medical College of Georgia, Augusta, GA 30912, USA Epigenetic silencing of tumor suppressor genes is a new focus of investigation in the generation and proliferation of carcinomas. Secreted protein acidic and rich in cysteine (SPARC) is reportedly detrimental to the growth of ovarian cancer cells and has been shown to be epigenetically silenced in several cancers. We hypothesized that SPARC is downregulated in ovarian cancer through aberrant promoter hypermethylation. To that end, we analyzed SPARC expression in ovarian cancer cell lines and investigated the methylation status of the Sparc promoter using methylation-specific polymerase chain reaction. Our results show that SPARC mRNA expression is decreased in three (33%) and absent in four (44%) of the nine ovarian cancer cell lines studied, which correlated with hypermethylation of the Sparc promoter. Treatment with the demethylating agent 5-aza-2′-deoxycytidine rescued SPARC mRNA and protein expression. Addition of exogenous SPARC, as well as ectopic expression by an adenoviral vector, resulted in decreased proliferation of ovarian cancer cell lines. Investigation of primary tumors revealed that the Sparc promoter is methylated in 68% of primary ovarian tumors and that the levels of SPARC protein decrease as the disease progresses from low to high grade. Lastly, de novo methylation of Sparc promoter was shown to be mediated by DNA methyltransferase 3a. These results implicate Sparc promoter methylation as an important factor in the genesis and survival of ovarian carcinomas and provide new insights into the potential use of SPARC as a novel biomarker and/or treatment modality for this disease. http://www.sciencedirect.com/science/article/pii/S1476558609800250 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Matthew J. Socha Neveen Said Yanshan Dai Joseph Kwong Preetha Ramalingam Vuong Trieu Neil Desai Samuel C. Mok Kouros Motamed |
spellingShingle |
Matthew J. Socha Neveen Said Yanshan Dai Joseph Kwong Preetha Ramalingam Vuong Trieu Neil Desai Samuel C. Mok Kouros Motamed Aberrant Promoter Methylation of Sparc in Ovarian Cancer Neoplasia: An International Journal for Oncology Research |
author_facet |
Matthew J. Socha Neveen Said Yanshan Dai Joseph Kwong Preetha Ramalingam Vuong Trieu Neil Desai Samuel C. Mok Kouros Motamed |
author_sort |
Matthew J. Socha |
title |
Aberrant Promoter Methylation of Sparc in Ovarian Cancer |
title_short |
Aberrant Promoter Methylation of Sparc in Ovarian Cancer |
title_full |
Aberrant Promoter Methylation of Sparc in Ovarian Cancer |
title_fullStr |
Aberrant Promoter Methylation of Sparc in Ovarian Cancer |
title_full_unstemmed |
Aberrant Promoter Methylation of Sparc in Ovarian Cancer |
title_sort |
aberrant promoter methylation of sparc in ovarian cancer |
publisher |
Elsevier |
series |
Neoplasia: An International Journal for Oncology Research |
issn |
1476-5586 1522-8002 |
publishDate |
2009-02-01 |
description |
Epigenetic silencing of tumor suppressor genes is a new focus of investigation in the generation and proliferation of carcinomas. Secreted protein acidic and rich in cysteine (SPARC) is reportedly detrimental to the growth of ovarian cancer cells and has been shown to be epigenetically silenced in several cancers. We hypothesized that SPARC is downregulated in ovarian cancer through aberrant promoter hypermethylation. To that end, we analyzed SPARC expression in ovarian cancer cell lines and investigated the methylation status of the Sparc promoter using methylation-specific polymerase chain reaction. Our results show that SPARC mRNA expression is decreased in three (33%) and absent in four (44%) of the nine ovarian cancer cell lines studied, which correlated with hypermethylation of the Sparc promoter. Treatment with the demethylating agent 5-aza-2′-deoxycytidine rescued SPARC mRNA and protein expression. Addition of exogenous SPARC, as well as ectopic expression by an adenoviral vector, resulted in decreased proliferation of ovarian cancer cell lines. Investigation of primary tumors revealed that the Sparc promoter is methylated in 68% of primary ovarian tumors and that the levels of SPARC protein decrease as the disease progresses from low to high grade. Lastly, de novo methylation of Sparc promoter was shown to be mediated by DNA methyltransferase 3a. These results implicate Sparc promoter methylation as an important factor in the genesis and survival of ovarian carcinomas and provide new insights into the potential use of SPARC as a novel biomarker and/or treatment modality for this disease.
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url |
http://www.sciencedirect.com/science/article/pii/S1476558609800250 |
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