Low MAD2 expression levels associate with reduced progression-free survival in patients with high-grade serous epithelial ovarian cancer.

Hdl Handle:
http://hdl.handle.net/10147/230232
Title:
Low MAD2 expression levels associate with reduced progression-free survival in patients with high-grade serous epithelial ovarian cancer.
Authors:
Furlong, Fiona; Fitzpatrick, Patricia; O'Toole, Sharon; Phelan, Sine; McGrogan, Barbara; Maguire, Aoife; O'Grady, Anthony; Gallagher, Michael; Prencipe, Maria; McGoldrick, Aloysius; McGettigan, Paul; Brennan, Donal; Sheils, Orla; Martin, Cara; W Kay, Elaine; O'Leary, John; McCann, Amanda
Affiliation:
UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. fiona.furlong@ucd.ie
Citation:
Low MAD2 expression levels associate with reduced progression-free survival in patients with high-grade serous epithelial ovarian cancer. 2012, 226 (5):746-55 J. Pathol.
Journal:
The Journal of pathology
Issue Date:
Apr-2012
URI:
http://hdl.handle.net/10147/230232
DOI:
10.1002/path.3035
PubMed ID:
22069160
Abstract:
Epithelial ovarian cancer (EOC) has an innate susceptibility to become chemoresistant. Up to 30% of patients do not respond to conventional chemotherapy [paclitaxel (Taxol®) in combination with carboplatin] and, of those who have an initial response, many patients relapse. Therefore, an understanding of the molecular mechanisms that regulate cellular chemotherapeutic responses in EOC cells has the potential to impact significantly on patient outcome. The mitotic arrest deficiency protein 2 (MAD2), is a centrally important mediator of the cellular response to paclitaxel. MAD2 immunohistochemical analysis was performed on 82 high-grade serous EOC samples. A multivariate Cox regression analysis of nuclear MAD2 IHC intensity adjusting for stage, tumour grade and optimum surgical debulking revealed that low MAD2 IHC staining intensity was significantly associated with reduced progression-free survival (PFS) (p = 0.0003), with a hazard ratio of 4.689. The in vitro analyses of five ovarian cancer cell lines demonstrated that cells with low MAD2 expression were less sensitive to paclitaxel. Furthermore, paclitaxel-induced activation of the spindle assembly checkpoint (SAC) and apoptotic cell death was abrogated in cells transfected with MAD2 siRNA. In silico analysis identified a miR-433 binding domain in the MAD2 3' UTR, which was verified in a series of experiments. Firstly, MAD2 protein expression levels were down-regulated in pre-miR-433 transfected A2780 cells. Secondly, pre-miR-433 suppressed the activity of a reporter construct containing the 3'-UTR of MAD2. Thirdly, blocking miR-433 binding to the MAD2 3' UTR protected MAD2 from miR-433 induced protein down-regulation. Importantly, reduced MAD2 protein expression in pre-miR-433-transfected A2780 cells rendered these cells less sensitive to paclitaxel. In conclusion, loss of MAD2 protein expression results in increased resistance to paclitaxel in EOC cells. Measuring MAD2 IHC staining intensity may predict paclitaxel responses in women presenting with high-grade serous EOC.
Item Type:
Article
Language:
en
MeSH:
3' Untranslated Regions; Antineoplastic Combined Chemotherapy Protocols; Calcium-Binding Proteins; Carboplatin; Cell Cycle Proteins; Cell Line, Tumor; Chemotherapy, Adjuvant; Disease-Free Survival; Dose-Response Relationship, Drug; Down-Regulation; Drug Resistance, Neoplasm; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; MicroRNAs; Multivariate Analysis; Neoplasm Grading; Neoplasm Staging; Neoplasms, Cystic, Mucinous, and Serous; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Paclitaxel; Paraffin Embedding; Proportional Hazards Models; RNA Interference; Repressor Proteins; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Transfection; Treatment Outcome; Tumor Markers, Biological
ISSN:
1096-9896

Full metadata record

DC FieldValue Language
dc.contributor.authorFurlong, Fionaen_GB
dc.contributor.authorFitzpatrick, Patriciaen_GB
dc.contributor.authorO'Toole, Sharonen_GB
dc.contributor.authorPhelan, Sineen_GB
dc.contributor.authorMcGrogan, Barbaraen_GB
dc.contributor.authorMaguire, Aoifeen_GB
dc.contributor.authorO'Grady, Anthonyen_GB
dc.contributor.authorGallagher, Michaelen_GB
dc.contributor.authorPrencipe, Mariaen_GB
dc.contributor.authorMcGoldrick, Aloysiusen_GB
dc.contributor.authorMcGettigan, Paulen_GB
dc.contributor.authorBrennan, Donalen_GB
dc.contributor.authorSheils, Orlaen_GB
dc.contributor.authorMartin, Caraen_GB
dc.contributor.authorW Kay, Elaineen_GB
dc.contributor.authorO'Leary, Johnen_GB
dc.contributor.authorMcCann, Amandaen_GB
dc.date.accessioned2012-06-22T12:45:45Z-
dc.date.available2012-06-22T12:45:45Z-
dc.date.issued2012-04-
dc.identifier.citationLow MAD2 expression levels associate with reduced progression-free survival in patients with high-grade serous epithelial ovarian cancer. 2012, 226 (5):746-55 J. Pathol.en_GB
dc.identifier.issn1096-9896-
dc.identifier.pmid22069160-
dc.identifier.doi10.1002/path.3035-
dc.identifier.urihttp://hdl.handle.net/10147/230232-
dc.description.abstractEpithelial ovarian cancer (EOC) has an innate susceptibility to become chemoresistant. Up to 30% of patients do not respond to conventional chemotherapy [paclitaxel (Taxol®) in combination with carboplatin] and, of those who have an initial response, many patients relapse. Therefore, an understanding of the molecular mechanisms that regulate cellular chemotherapeutic responses in EOC cells has the potential to impact significantly on patient outcome. The mitotic arrest deficiency protein 2 (MAD2), is a centrally important mediator of the cellular response to paclitaxel. MAD2 immunohistochemical analysis was performed on 82 high-grade serous EOC samples. A multivariate Cox regression analysis of nuclear MAD2 IHC intensity adjusting for stage, tumour grade and optimum surgical debulking revealed that low MAD2 IHC staining intensity was significantly associated with reduced progression-free survival (PFS) (p = 0.0003), with a hazard ratio of 4.689. The in vitro analyses of five ovarian cancer cell lines demonstrated that cells with low MAD2 expression were less sensitive to paclitaxel. Furthermore, paclitaxel-induced activation of the spindle assembly checkpoint (SAC) and apoptotic cell death was abrogated in cells transfected with MAD2 siRNA. In silico analysis identified a miR-433 binding domain in the MAD2 3' UTR, which was verified in a series of experiments. Firstly, MAD2 protein expression levels were down-regulated in pre-miR-433 transfected A2780 cells. Secondly, pre-miR-433 suppressed the activity of a reporter construct containing the 3'-UTR of MAD2. Thirdly, blocking miR-433 binding to the MAD2 3' UTR protected MAD2 from miR-433 induced protein down-regulation. Importantly, reduced MAD2 protein expression in pre-miR-433-transfected A2780 cells rendered these cells less sensitive to paclitaxel. In conclusion, loss of MAD2 protein expression results in increased resistance to paclitaxel in EOC cells. Measuring MAD2 IHC staining intensity may predict paclitaxel responses in women presenting with high-grade serous EOC.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to The Journal of pathologyen_GB
dc.subject.mesh3' Untranslated Regions-
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols-
dc.subject.meshCalcium-Binding Proteins-
dc.subject.meshCarboplatin-
dc.subject.meshCell Cycle Proteins-
dc.subject.meshCell Line, Tumor-
dc.subject.meshChemotherapy, Adjuvant-
dc.subject.meshDisease-Free Survival-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshDown-Regulation-
dc.subject.meshDrug Resistance, Neoplasm-
dc.subject.meshFemale-
dc.subject.meshHumans-
dc.subject.meshImmunohistochemistry-
dc.subject.meshKaplan-Meier Estimate-
dc.subject.meshMicroRNAs-
dc.subject.meshMultivariate Analysis-
dc.subject.meshNeoplasm Grading-
dc.subject.meshNeoplasm Staging-
dc.subject.meshNeoplasms, Cystic, Mucinous, and Serous-
dc.subject.meshNeoplasms, Glandular and Epithelial-
dc.subject.meshOvarian Neoplasms-
dc.subject.meshPaclitaxel-
dc.subject.meshParaffin Embedding-
dc.subject.meshProportional Hazards Models-
dc.subject.meshRNA Interference-
dc.subject.meshRepressor Proteins-
dc.subject.meshRetrospective Studies-
dc.subject.meshRisk Assessment-
dc.subject.meshRisk Factors-
dc.subject.meshTime Factors-
dc.subject.meshTransfection-
dc.subject.meshTreatment Outcome-
dc.subject.meshTumor Markers, Biological-
dc.titleLow MAD2 expression levels associate with reduced progression-free survival in patients with high-grade serous epithelial ovarian cancer.en_GB
dc.typeArticleen
dc.contributor.departmentUCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. fiona.furlong@ucd.ieen_GB
dc.identifier.journalThe Journal of pathologyen_GB
dc.description.provinceLeinsteren

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