The clinical role of phospholipase A2 isoforms in advanced-stage ovarian carcinoma
Michal Gorovetz1, Mark Baekelandt, Aasmund Berner
1Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel, and Department of Gynecologic Oncology, National Hospital-Norwegian Radium Hospital, Oslo, Norway.
Objective:
To analyze the expression of phospholipase A2 (PLA2) isoforms and its relationship with matrix metalloproteinase (MMP) expression and clinical parameters in advanced-stage (FIGO III-IV) ovarian carcinoma.
Methods:
Seventy-seven fresh frozen effusions from ovarian carcinoma patients were studied for messenger RNA (mRNA) expression of 10 secretory PLA2 (sPLA2) isoforms (IB, IIA/D/E/F, III, V, X, XII and XIII), the PLA2 receptor (sPLA2R), cytoplasmic PLA2 (cPLA2), PLA2-activating protein (PLAP) and MMP-2 using reverse transcription polymerase chain reaction (RT-PCR). Phosphorylated cPLA2 (p-cPLA2) protein expression was studied in 52 effusions using immunohistochemistry. MMP-2 and MMP-9 activity was evaluated in 22 and 20 effusions, respectively, using zymography. Expression was analyzed for correlation with clinicopathologic parameters, chemotherapy status and survival.
Results:
PLA2 isoforms, sPLA2R, PLAP and MMP-2 mRNA was expressed in >95% of specimens. p-cPLA2 protein was expressed in 46/52 (88%) effusions. MMP-2 activity was found in all specimens, while that of MMP-9 was detected in 19/20 effusions. MMP-2 was found to be co-expressed with p-cPLA2 (p=0.003) and sPLA2-IIA (p=0.021). Lower expression of sPLA2-IIA (p<0.001) and higher expression of sPLA2-V (p=0.038) and sPLA2-XIII (p=0.001) was found in post-chemotherapy effusions. In univariate survival analysis, higher levels of sPLA2-V correlated with better overall (OS, p=0.021) and progression-free (PFS, p=0.025) survival. For patients with post-chemotherapy effusions, FIGO stage IV and higher PLAP mRNA expression correlated with worse OS (p=0.005 for both PLAP and stage), while higher PLAP (p=0.025) and sPLA2-XII (p=0.027) levels and FIGO stage IV (p<0.001) correlated with shorter PFS. In Cox multivariate analysis, PLAP expression (p=0.022) and FIGO stage (p=0.036) independently predicted poor OS, while higher sPLA2-XII levels (p=0.04) and FIGO stage (p=0.003) were independent predictors of shorter PFS.
Conclusions:
The present study documents for the first time expression of PLA2 isoforms, sPLA2R and PLAP in ovarian carcinoma. PLA2 isoenzyme expression differs in pre- and post-chemotherapy specimens. PLAP and sPLA2-XII may be independent predictors of poor outcome for patients with post-chemotherapy effusions.
