The clinical role of phospholipase A2 isoforms in advanced-stage ovarian carcinoma

Abstract

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. 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. 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. 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.