Type

Journal Article

Authors

Amanda McCann
John O'Leary
Elaine W Kay
Cara Martin
Orla Sheils
Donal Brennan
Paul McGettigan
Aloysius McGoldrick
Maria Prencipe
Michael Gallagher
and 7 others

Subjects

Microbiology

Topics
therapeutic use therapy metabolism mad2l1 protein human humans disease free survival ovarian neoplasms down regulation micrornas retrospective studies repressor proteins drug therapy female neoplasms glandular and epithelial risk assessment cell cycle proteins genetics pathology neoplasm staging antineoplastic combined chemotherapy protocols chemotherapy adjuvant treatment outcome rna interference mirn433 microrna human proportional hazards models administration dosage calcium binding proteins mortality risk factors tumor markers biological 3 untranslated regions drug resistance neoplasm kaplan meier estimate neoplasm grading time factors cell line tumor dose response relationship drug immunohistochemistry carboplatin paraffin embedding multivariate analysis transfection paclitaxel neoplasms cystic mucinous and serous

Low MAD2 expression levels associate with reduced progression-free survival in patients with high-grade serous epithelial ovarian cancer. (2011)

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.
Collections Ireland -> University College Dublin -> PubMed

Full list of authors on original publication

Amanda McCann, John O'Leary, Elaine W Kay, Cara Martin, Orla Sheils, Donal Brennan, Paul McGettigan, Aloysius McGoldrick, Maria Prencipe, Michael Gallagher and 7 others

Experts in our system

1
Amanda McCann
University College Dublin
Total Publications: 41
 
2
John O'Leary
Trinity College Dublin
Total Publications: 93
 
3
Elaine W Kay
Royal College of Surgeons in Ireland
Total Publications: 157
 
4
Cara Martin
Trinity College Dublin
Total Publications: 49
 
5
Orla Sheils
Trinity College Dublin
Total Publications: 55
 
6
Donal J Brennan
University College Dublin
 
7
Paul A. McGettigan
University College Dublin
Total Publications: 46
 
8
Aloysius McGoldrick
University College Dublin
Total Publications: 9
 
9
Maria Prencipe
University College Dublin
Total Publications: 19
 
10
Michael Gallagher
Trinity College Dublin
Total Publications: 21