Expression of Secretory Phospholipase A2 Group IIa in Breast Cancer and Correlation to Prognosis in a Cohort of Advanced Breast Cancer Patients.

Secreted phospholipase A2 group IIa (sPLA2-IIa) has been shown to promote tumor genesis and cell proliferation. The properties of this group of enzymes are utilized in liposomal drug delivery of chemotherapy. sPLA2-IIa is also under investigation as a possible treatment target in itself, and as a prognostic marker. The expression of sPLA2-IIa in breast cancer has not been examined extensively, and never using immunohistochemistry. We sought to investigate the expression of sPLA2-IIa in a cohort of advanced breast cancer patients with correlation to known clinicopathologic risk factors and survival. Material from 525 breast cancer patients (426 primary tumors and 99 metastases or local recurrences) was examined for sPLA2-IIa expression using immunohistochemistry. Out of these, 262 showed expression of sPLA2-IIa. We found that there was no correlation to clinicopathologic characteristics, and no impact of sPLA2-IIa expression on prognosis. However, we found that a large proportion of patients in our study had high levels of sPLA2-IIa expression, and that sPLA2-IIa was equally expressed in primary tumors and metastases. These findings may be significant in the future development of liposomal drug delivery or targeted sPLA2-IIa treatment.

Expression and Function of Group IIE Phospholipase A2 in Mouse Skin.

Recent studies using knock-out mice for various secreted phospholipase A2 (sPLA2) isoforms have revealed their non-redundant roles in diverse biological events. In the skin, group IIF sPLA2 (sPLA2-IIF), an "epidermal sPLA2" expressed in the suprabasal keratinocytes, plays a fundamental role in epidermal-hyperplasic diseases such as psoriasis and skin cancer. In this study, we found that group IIE sPLA2 (sPLA2-IIE) was expressed abundantly in hair follicles and to a lesser extent in basal epidermal keratinocytes in mouse skin. Mice lacking sPLA2-IIE exhibited skin abnormalities distinct from those in mice lacking sPLA2-IIF, with perturbation of hair follicle ultrastructure, modest changes in the steady-state expression of a subset of skin genes, and no changes in the features of psoriasis or contact dermatitis. Lipidomics analysis revealed that sPLA2-IIE and -IIF were coupled with distinct lipid pathways in the skin. Overall, two skin sPLA2s, hair follicular sPLA2-IIE and epidermal sPLA2-IIF, play non-redundant roles in distinct compartments of mouse skin, underscoring the functional diversity of multiple sPLA2s in the coordinated regulation of skin homeostasis and diseases.

Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality.

Preterm labour (PTL) is commonly associated with infection and/or inflammation. Lipopolysaccharide (LPS) from different bacteria can be used to independently or mutually activate Jun N-terminal kinase (JNK)/AP1- or NF-κB-driven inflammatory pathways that lead to PTL. Previous studies using Salmonella abortus LPS, which activates both JNK/AP-1 and NF-κB, showed that selective inhibition of NF-κB delays labour and improves pup outcome. Where labour is induced using Escherichia coli LPS (O111), which upregulates JNK/AP-1 but not NF-κB, inhibition of JNK/AP-1 activation also delays labour. In this study, to determine the potential role of JNK as a therapeutic target in PTL, we investigated the specific contribution of JNK signalling to S. Abortus LPS-induced PTL in mice. Intrauterine administration of S. Abortus LPS to pregnant mice resulted in the activation of JNK in the maternal uterus and fetal brain, upregulation of pro-inflammatory proteins COX-2, CXCL1, and CCL2, phosphorylation of cPLA2 in myometrium, and induction of PTL. Specific inhibition of JNK by co-administration of specific D-JNK inhibitory peptide (D-JNKI) delayed LPS-induced preterm delivery and reduced fetal mortality. This is associated with inhibition of myometrial cPLA2 phosphorylation and proinflammatory proteins synthesis. In addition, we report that D-JNKI inhibits the activation of JNK/JNK3 and caspase-3, which are important mediators of neural cell death in the neonatal brain. Our data demonstrate that specific inhibition of TLR4-activated JNK signalling pathways has potential as a therapeutic approach in the management of infection/inflammation-associated PTL and prevention of the associated detrimental effects to the neonatal brain.

Staphylococcus aureus Adenosine Inhibits sPLA2-IIA-Mediated Host Killing in the Airways.

Staphylococcus aureus is a common cause of bacterial infections in respiratory diseases. It secretes molecules to dampen host immunity, and the recently identified adenosine is one of these molecules. The type IIA secretory phospholipase A2 (sPLA2-IIA) is a host protein endowed with antibacterial properties, especially against Gram-positive bacteria such as S. aureus. However, the role of adenosine in sPLA2-IIA-mediated S. aureus killing by host is still unknown. The present studies showed that the S. aureus mutant lacking adenosine production (∆adsA strain) increased sPLA2-IIA expression in guinea pig airways and was cleared more efficiently, compared with the wild-type strain. S. aureus ∆adsA strain induced sPLA2-IIA expression by alveolar macrophages after phagocytic process via NOD2-NF-κB-dependent mechanism. However, S. aureus adenosine (wild-type and adsA-complemented strains) and exogenous adenosine downregulated S. aureus phagocytosis by alveolar macrophages, leading to inhibition of sPLA2-IIA expression. This occurred through inhibition of p38 phosphorylation via adenosine receptors A2a-, A2b-, and protein kinase A-dependent pathways. Taken together, our studies suggest that, in the airway, S. aureus escapes sPLA2-IIA-mediated killing through adenosine-mediated inhibition of phagocytosis and sPLA2-IIA expression.

Inhibitory Effect of FXa on Secretory Group IIA Phospholipase A2.

It is well known that the expression level of secretory group IIA phospholipase A2 (sPLA2-IIA) is elevated in inflammatory diseases and lipopolysaccharide (LPS) upregulates the expression of sPLA2-IIA in human umbilical vein endothelial cells (HUVECs). Activated factor X (FXa) is an important enzyme in the coagulation cascade responsible for thrombin generation, and it influences cell signaling in various cell types by activating protease-activated receptors (PARs). Here, FX or FXa was examined for its effects on the expression and activity of sPLA2-IIA in HUVECs and mouse. Prior treatment of cells or mouse with FXa inhibited LPS-induced expression and activity of sPLA2-IIA via interacting with FXa receptor (effective cell protease receptor-1, EPR-1). And FXa suppressed the activation of cytosolic phospholipase A2 (cPLA2) and extracellular signal-regulated kinase (ERK) 1/2 by LPS. Therefore, these results suggest that FXa may inhibit LPS-mediated expression of sPLA2-IIA by suppression of cPLA2 and ERK 1/2.

Group IIa secretory phospholipase A2 (sPLA2IIa) and progression in patients with lung cancer.

OBJECTIVE: Group IIa secretory phospholipase A2 (sPLA2 IIa) plays a role in the malignant potential of several epithelial cancers. It is overexpressed in many cancer specimens and its elevated levels are correlated with high tumor grade and metastasis. Here, we evaluate the clinical significance of sPLA2 IIa in lung adenocarcinoma and the role of sPLA2 IIa in the process of cancer cell invasion and metastasis. PATIENTS AND METHODS: Immunohistochemistry was used to investigate sPLA2 IIa in surgically resected lung adenocarcinoma of 180 patients and its correlation with survival. We overexpressed sPLA2 IIa in a lung adenocarcinoma cell line with very low sPLA2 IIa levels and investigated the in vitro and in vivo effects of sPLA2 IIa expression. RESULTS: High expression of sPLA2 IIa in lung cancer tissue was significantly associated with clinical stage, metastasis, postoperative relapse and shorter patient survival. The overexpression of sPLA2 IIa enhanced xenograft tumor growth and invasion in vitro. CONCLUSIONS: sPLA2 IIa expression can predict the clinical outcome of lung adenocarcinoma patients. sPLA2 IIa is a novel invasion-promoting gene in lung adenocarcinoma.

Nuclear corepressors mediate the repression of phospholipase A2 group IIa gene transcription by thyroid hormone.

Secretory phospholipase A2 group IIa (PLA2g2a) is associated with inflammation, hyperlipidemia, and atherogenesis. Transcription of the PLA2g2a gene is induced by multiple cytokines. Here, we report the surprising observation that thyroid hormone (T3) inhibited PLA2g2a gene expression in human and rat hepatocytes as well as in rat liver. Moreover, T3 reduced the cytokine-mediated induction of PLA2g2a, suggesting that the thyroid status may modulate aspects of the inflammatory response. In an effort to dissect the mechanism of repression by T3, we cloned the PLA2g2a gene and identified a negative T3 response element in the promoter. This T3 receptor (TRß)-binding site differed considerably from consensus T3 stimulatory elements. Using in vitro and in vivo binding assays, we found that TRß bound directly to the PLA2g2a promoter as a heterodimer with the retinoid X receptor. Knockdown of nuclear corepressor or silencing mediator for retinoid and thyroid receptors by siRNA blocked the T3 inhibition of PLA2g2a. Using chromatin immunoprecipitation assays, we showed that nuclear corepressor and silencing mediator for retinoid and thyroid receptors were associated with the PLA2g2a gene in the presence of T3. In contrast with the established role of T3 to promote coactivator association with TRß, our experiments demonstrate a novel inverse recruitment mechanism in which liganded TRß recruits corepressors to inhibit PLA2g2a expression.

Clinical significance of phospholipase A2 group IIA (PLA2G2A) expression in primary resected esophageal squamous cell carcinoma.

AIM: The aim of this study was to clarify the clinico-pathological outcome and prognostic significance of phospholipase A2 group IIA (PLA2G2A) in esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Immunohistochemical staining for PLA2G2A was performed on surgical specimens obtained from 132 patients with ESCC, and 43 from matched adjacent non-malignant sites. Differences in PLA2G2A expression and clinical characteristics were compared by χ2 test. Correlations between prognostic outcomes and with PLA2G2A expression were investigated using Kaplan-Meier analysis and the Cox proportional hazards model. RESULTS: Immunoreactivity of PLA2G2A was observed in 32% (42 of 132) of ESCC tissues compared with negative staining in matched adjacent non-malignant sites. In addition, PLA2G2A expression inversely correlated with pathological classification (p < 0.05 for T, N, and M classifications) and clinical staging (p = 0.03). Furthermore, patients with positive PLA2G2A had prolonged overall survival (p < 0.01). CONCLUSIONS: Reduced PLA2G2A expression may be a risk factor for advanced clinicopathological classification and poor patient survival. These findings suggest that PLA2G2A may serve as a useful marker for the prognostic evaluation of ESCC patients.

Regulatory effects of the JAK3/STAT1 pathway on the release of secreted phospholipase A2-IIA in microvascular endothelial cells of the injured brain.

BACKGROUND: Secreted phospholipase A2-IIA (sPLA2-IIA) is an inducible enzyme released under several inflammatory conditions. It has been shown that sPLA2-IIA is released from rat brain astrocytes after inflammatory stimulus, and lipopolysaccharide (LPS) and nitric oxide (NO) have been implicated in regulation of this release. Here, brain microvascular endothelial cells (BMVECs) were treated with LPS to uncover whether sPLA2-IIA was released, whether nitric oxide regulated this release, and any related signal mechanisms. METHODS: Supernatants were collected from primary cultures of BMVECs. The release of sPLA2-IIA, and the expression of inducible nitric oxide synthase (iNOS), phospho-JAK3, phospho-STAT1, total JAK3 and STAT1, ß-actin, and bovine serum albumin (BSA) were analyzed by Western blot or ELISA. NO production was calculated by the Griess reaction. sPLA2 enzyme activity was measured with a fluorometric assay. Specific inhibitors of NO (L-NAME and aminoguanidine, AG), JAK3 (WHI-P154,WHI), STAT1 (fludarabine, Flu), and STAT1 siRNA were used to determine the involvement of these molecules in the LPS-induced release of sPLA2-IIA from BMVECs. Nuclear STAT1 activation was tested with the EMSA method. The monolayer permeability of BMVECs was measured with a diffusion assay using biotinylated BSA. RESULTS: Treatment of BMVECs with LPS increased the release of sPLA2-IIA and nitrite into the cell culture medium up to 24 h. Pretreatment with an NO donor, sodium nitroprusside, decreased LPS-induced sPLA2-IIA release and sPLA2 enzyme activity, and enhanced the expression of iNOS and nitrite generation after LPS treatment. Pretreatment with L-NAME, AG, WHI-P154, or Flu notably reduced the expression of iNOS and nitrite, but increased sPLA2-IIA protein levels and sPLA2 enzyme activity. In addition, pretreatment of the cells with STAT1 siRNA inhibited the phosphorylation of STAT1, iNOS expression, and nitrite production, and enhanced the release of sPLA2-IIA. Pretreatment with the specific inhibitors of NOS, JAK2, and STAT3 decreased the permeability of BMVECs. In contrast, inhibition of sPLA2-IIA release increased cell permeability. These results suggest that sPLA2-IIA expression is regulated by the NO-JAK3-STAT1 pathway. Importantly, sPLA2-IIA augmentation could protect the LPS-induced permeability of BMVECs. CONCLUSION: Our results demonstrate the important action of sPLA2-IIA in the permeability of microvascular endothelial cells during brain inflammatory events. The sPLA2 and NO pathways can be potential targets for the management of brain MVEC injuries and related inflammation.

Secretory phospholipase A2 responsive liposomes.

Secretory phospholipase A(2) (sPLA(2)) expression is increased in several cancers and has been shown to trigger release from some lipid carriers. This study used electrospray ionization mass spectrometry (ESI-MS) and release of 6-carboxyfluorescein (6-CF) to determine the effects of sPLA(2) on various liposome formulations. Different combinations of zwitterionic [1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, 1,2-distearoyl-sn-glycero-3-phosphatidylcholine, and 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE)] and anionic [1,2-distearoyl-sn-glycero-3-phosphatidic acid, 1,2-distearoyl-sn-glycero-3-phosphatidylglycerol (DSPG), 1,2-distearoyl-sn-glycero-3-phosphatidylserine, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-poly(ethylene glycol) 2000 (DSPE-PEG)] phospholipids were examined. DSPG and DSPE were most susceptible to sPLA(2)-mediated degradation compared with other phospholipids. Increased 6-CF release was observed after inclusion of 10 mol % DSPE and anionic lipids into different liposome formulations. Group IIa sPLA(2)-mediated 6-CF release was less than Group III and relatively insensitive to cholesterol (Chol), whereas Chol reduced sPLA(2)-mediated release. Inclusion of DSPE-PEG increased sPLA(2)-mediated 6-CF release, whereas serum reduced lipid degradation and 6-CF release significantly. These data demonstrate that ESI-MS and 6-CF release were useful in determining the selectivity of sPLA(2) and release from liposomes, that differences in the activity of different sPLA(2) isoforms exist, and that DSPE-PEG enhanced sPLA(2)-mediated release of liposomal constituents. These findings will aid in the selection of lipids and optimization of the kinetics of drug release for the treatment of cancers and diseases of inflammation in which sPLA(2) expression is increased.

Vav3 oncogene is involved in regulation of secretory phospholipase A2-IIa expression in prostate cancer.

Our previous study revealed that Vav3 oncogene and secretory phospholipase A2-IIa (sPLA2-IIa) are overexpressed in androgen-independent prostate cancer cells relative to their androgen-dependent counterparts and contribute to development of hormone refractory prostate cancer. Vav3 is a multiple function protein with both signaling molecule and coactivator activities. sPLA2-IIa is a downstream effector of HER/HER2-PI3K-Akt-NF-κB signaling and involved in inflammatory response and tumorigenesis. The aim of the current study was to determine whether Vav3 is involved in up-regulation of sPLA2-IIa expression, given that Vav3 signals in the HER/HER2-elicited pathway. Among 46 prostate cancer specimens examined, Vav3 and sPLA2-IIa are overexpressed in 48 and 83% human prostate cancers, respectively. Vav3 overexpression is significantly associated with a high level expression of sPLA2-IIa. In addition, significant Vav3 nuclear localization is observed in two prostate cancer specimens, supporting a coactivator activity in prostate cancer cells. Further analysis revealed that Vav3 up-regulates expression of the sPLA2-IIa gene at the transcriptional level via HER/HER2-PI3K-Akt-NF-κB signaling. These data revealed that Vav3 overexpression as an additional underlying mechanism contributes to elevated sPLA2-IIa expression in prostate cancer.

Production of vascular endothelial growth factors from human lung macrophages induced by group IIA and group X secreted phospholipases A2.

Angiogenesis and lymphangiogenesis mediated by vascular endothelial growth factors (VEGFs) are main features of chronic inflammation and tumors. Secreted phospholipases A(2) (sPLA(2)s) are overexpressed in inflammatory lung diseases and cancer and they activate inflammatory cells by enzymatic and receptor-mediated mechanisms. We investigated the effect of sPLA(2)s on the production of VEGFs from human macrophages purified from the lung tissue of patients undergoing thoracic surgery. Primary macrophages express VEGF-A, VEGF-B, VEGF-C, and VEGF-D at both mRNA and protein level. Two human sPLA(2)s (group IIA and group X) induced the expression and release of VEGF-A and VEGF-C from macrophages. Enzymatically-inactive sPLA(2)s were as effective as the active enzymes in inducing VEGF production. Me-Indoxam and RO092906A, two compounds that block receptor-mediated effects of sPLA(2)s, inhibited group X-induced release of VEGF-A. Inhibition of the MAPK p38 by SB203580 also reduced sPLA(2)-induced release of VEGF-A. Supernatants of group X-activated macrophages induced an angiogenic response in chorioallantoic membranes that was inhibited by Me-Indoxam. Stimulation of macrophages with group X sPLA(2) in the presence of adenosine analogs induced a synergistic increase of VEGF-A release and inhibited TNF-alpha production through a cooperation between A(2A) and A(3) receptors. These results demonstrate that sPLA(2)s induce production of VEGF-A and VEGF-C in human macrophages by a receptor-mediated mechanism independent from sPLA(2) catalytic activity. Thus, sPLA(2)s may play an important role in inflammatory and/or neoplastic angiogenesis and lymphangiogenesis.

Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cholesterol transport during the acute phase response but not group IIA secretory phospholipase A(2).

Atherosclerosis is linked to inflammation. HDL protects against atherosclerotic cardiovascular disease, mainly by mediating cholesterol efflux and reverse cholesterol transport (RCT). The present study aimed to test the impact of acute inflammation as well as selected acute phase proteins on RCT with a macrophage-to-feces in vivo RCT assay using intraperitoneal administration of [(3)H]cholesterol-labeled macrophage foam cells. In patients with acute sepsis, cholesterol efflux toward plasma and HDL were significantly decreased (P < 0.001). In mice, acute inflammation (75 microg/mouse lipopolysaccharide) decreased [(3)H]cholesterol appearance in plasma (P < 0.05) and tracer excretion into feces both within bile acids (-84%) and neutral sterols (-79%, each P < 0.001). In the absence of systemic inflammation, overexpression of serum amyloid A (SAA, adenovirus) reduced overall RCT (P < 0.05), whereas secretory phospholipase A(2) (sPLA(2), transgenic mice) had no effect. Myeloperoxidase injection reduced tracer appearance in plasma (P < 0.05) as well as RCT (-36%, P < 0.05). Hepatic expression of bile acid synthesis genes (P < 0.01) and transporters mediating biliary sterol excretion (P < 0.01) was decreased by inflammation. In conclusion, our data demonstrate that acute inflammation impairs cholesterol efflux in patients and macrophage-to-feces RCT in vivo in mice. Myeloperoxidase and SAA contribute to a certain extent to reduced RCT during inflammation but not sPLA(2). However, reduced bile acid formation and decreased biliary sterol excretion might represent major contributing factors to decreased RCT in inflammation.

Anthrax lethal toxin down-regulates type-IIA secreted phospholipase A(2) expression through MAPK/NF-kappaB inactivation.

Bacillus anthracis, the etiological agent of anthrax, produces lethal toxin (LT) that displays a metallo-proteolytic activity toward the N-terminus of the MAPK-kinases. We have previously shown that secreted type-IIA phospholipase A(2) (sPLA(2)-IIA) exhibits potent anthracidal activity. In vitro expression of sPLA(2)-IIA in guinea pig alveolar macrophages (AMs), the major source of this enzyme in lung tissues, is inhibited by LT. Here, we examined the mechanisms involved in sPLA(2)-IIA inhibition by LT. We first showed that chemical inhibitors of p38 and ERK MAPKs reduced sPLA(2)-IIA expression in AMs indicating that these kinases play a role in sPLA(2)-IIA expression. LT inhibited IL-1beta-induced p38 phosphorylation as well as sPLA(2)-IIA promoter activity in CHO cells. Inhibition of sPLA(2)-IIA promoter activity was mimicked by co-transfection with dominant negative construct of p38 (DN-p38) and reversed by the active form of p38-MAPK (AC-p38). Both LT and DN-p38 decreased IL-1beta-induced NF-kappaB luciferase activity. This contrasted with the effect of AC-p38, which enhanced this activity. However, neither LT nor specific p-38 inhibitor interfered with LPS-induced IkappaBalpha degradation or NF-kappaB nuclear translocation in AMs. Subcutaneous administration of LT to guinea pig before LPS challenge reduced sPLA(2)-IIA levels in broncho-alveolar lavages and ears. We conclude that sPLA(2)-IIA expression is induced via a sequential MAPK-NF-kappaB activation and that LT inhibits this expression likely by interfering with the transactivation of NF-kappaB in the nucleus. This inhibition, which is operating both in vitro and in vivo, may represent a mechanism by which B. anthracis subvert host defense.

Secretory type II phospholipase A2 is produced and secreted by epicardial adipose tissue and overexpressed in patients with coronary artery disease.

CONTEXT: Epicardial adipose tissue (EAT) is a visceral adipose tissue in close contact with coronary vessels, the excess of which is associated with coronary artery disease (CAD). OBJECTIVE: Our goal was to identify candidate molecule(s) characterizing EAT that could intervene in the pathogenesis of CAD. DESIGN: An approach combining microarrays and bioinformatic sequence analysis tools for predicting secreted proteins (TargetP) was applied to paired biopsies of sc adipose tissue (SAT) and EAT, obtained from patients with or without CAD (NCAD). RESULTS were validated in three independent groups of subjects by quantitative RT-PCR, Western blot, immunohistochemistry, and explant secretion. RESULTS: Secretory type II phospholipase A2 (sPLA2-IIA) ranked as the highest gene coding for potentially secreted proteins with the highest overexpression in EAT in both CAD and NCAD. Quantitative RT-PCR confirmed its increased expression in EAT (P < 0.01) as well as EAT from CAD as compared with NCAD (49.3 +/- 13 vs. 17.4 +/- 9.7 P < 0.01). sPLA2-IIA protein levels were higher in EAT than SAT (P < 0.001). EAT explants also showed significantly higher sPLA2-IIA secretion levels than SAT ones (4.37 +/- 2.7 vs. 0.67 +/- 0.28 ng/ml to 1 per gram tissue per 24 h, P < 0.03). sPLA2-IIA labeling was seen in the stroma vascular fraction between adipocytes and in connective capsules in EAT, with no immunostaining of the adipocytes. SAT was weakly labeled following the same process. CONCLUSION: We have shown for the first time an increased expression of sPLA2-IIA in EAT in patients with CAD. sPLA2-IIA is a phospholipase, which has been shown to be an independent risk factor for CAD. These findings suggest that EAT has a potentially pathophysiological role in CAD.

Group IIA phospholipase A as a prognostic marker in prostate cancer: relevance to clinicopathological variables and disease-specific mortality.

Group IIA Phospholipase A(2) (PLA2-IIA), a key enzyme in arachidonic acid and eicosanoid metabolism, participates in a variety of inflammatory processes but possibly also plays a role in tumor progression in vivo. Our aim was to determine the mRNA and protein expression of PLA2-IIA during prostate cancer progression in localized and metastatic prostate tumors. We evaluated the prognostic significance of PLA2-IIA expression in biochemical recurrence, clinical recurrence and disease-specific survival after surgical treatment. The expression of PLA2-IIA was examined by immunohistochemistry and chromogenic in situ hybridization in tissue microarrays of radical prostatectomy specimens and advanced/metastatic carcinomas. The expression data were analyzed in conjunction with clinical follow-up information and clinicopathological variables. The mRNA and protein expression of PLA2-IIA was significantly increased in Gleason pattern grade 2-4 carcinomas compared with benign prostate (p-values 0.042-0.001). In metastases, the expression was significantly lower than in local cancers (p=0.001). The PLA2-IIA expression correlated positively with Ki-67 and alpha-methylacyl CoA racemase (AMACR) expression. The prognostic evaluation revealed decreased PLA2-IIA protein expression among patients who had died of prostate cancer. In conclusion, PLA2-IIA expression is increased in carcinoma when compared with benign prostate. However, metastatic carcinoma showed decreased expression of PLA2-IIA when compared with primary carcinomas. PLA2-IIA may serve as a marker for highly proliferating, possibly poorly differentiated prostate carcinomas. The protein expression of PLA2-IIA may be diminished in patients who consequently die of prostate cancer.

Correlation between sPLA2-IIA and phosgene-induced rat acute lung injury.

Secreted phospholipase A(2) of group IIA (sPLA(2)-IIA) has been involved in a variety of inflammatory diseases, including acute lung injury. However, the specific role of sPLA(2)-IIA in phosgene-induced acute lung injury remains unidentified. The aim of the present study was to investigate the correlation between sPLA(2)-IIA activity and the severity of phosgene-induced acute lung injury. Adult male rats were randomly exposed to either normal room air (control group) or a concentration of 400 ppm phosgene (phosgene-exposed group) for there are 5 phosgene-exposed groups altogether. For the time points of 1, 3, 6, 12 and 24 h post-exposure, one phosgene-exposed group was sacrificed at each time point. The severity of acute lung injury was assessed by Pa(O2)/F(IO2) ratio, wet-to-dry lung-weight ratio, and bronchoalveolar lavage (BAL) fluid protein concentration. sPLA(2)-IIA activity in BAL fluid markedly increased between 1 h and 12 h after phosgene exposure, and reached its highest level at 6 h. Moreover, the trend of this elevation correlated well with the severity of lung injury. These results indicate that sPLA(2)-IIA probably participates in phosgene-induced acute lung injury.

Increased expression and activity of group IIA and X secretory phospholipase A2 in peritumoral versus central colon carcinoma tissue.

Secretory phospholipase A2 (sPLA2) type IIA and X was analyzed in tumors from 22 patients with colon adenocarcinomas in order to determine the involvement and activity of sPLA2 in colon cancer. Evaluation of immunoreactive sPLA2 IIA by Western blotting showed a significantly higher level in the periphery of the tumors, compared to central tumor regions. Increased levels of sPLA2 IIA protein correlated with a two-fold increase in sPLA2 enzymatic activity in the peripheral regions compared to central regions. Nineteen out of 22 tumors showed high levels of sPLA2 IIA, whereas 7 out of the 22 tumors showed sPLA2 type X. These data demonstrate that both sPLA2 type IIA and X are present in human colon cancer and suggest a role for sPLA2 in colon cancer tumor immunology and tumorigenesis.

Inhibition of interleukin-1beta-induced group IIA secretory phospholipase A2 expression by peroxisome proliferator-activated receptors (PPARs) in rat vascular smooth muscle cells: cooperation between PPARbeta and the proto-oncogene BCL-6.

The inflammation that occurs during atherosclerosis is characterized by the release of large amounts of group IIA secretory phospholipase A2 (sPLA2-IIA). This study was designed to define the function of the three peroxisome proliferator-activated receptors (PPARs) on sPLA2 expression in vascular smooth muscle cells (VSMCs). We found that PPAR ligands decreased sPLA2-IIA activity and inhibited mRNA accumulation under inflammatory conditions. Furthermore, interleukin-1beta-induced sPLA2-IIA promoter activity was inhibited by the three PPAR ligands and in a similar way when cells were cotransfected with PPARalpha, PPARbeta, or PPARgamma, plus retinoid X receptor alpha (RXRalpha). Our study revealed that the regulation of sPLA2-IIA gene transcription by PPARalpha/RXR and PPARgamma/RXR heterodimers requires an interaction with a PPAR response element (PPRE) of the sPLA2-IIA promoter. In contrast, PPARbeta operates through a PPRE-independent mechanism. In addition, we demonstrated that VSMCs expressed the transcriptional repressor BCL-6. Overexpression of BCL-6 markedly reduced sPLA2-IIA promoter activity in VSMCs, while a dominant negative form of BCL-6 abrogated sPLA2 repression by PPARbeta. The PPARbeta agonist induced a BCL-6 binding to the sPLA2 promoter in VSMCs under inflammatory conditions. The knockdown of BCL-6 by short interfering RNA abolished the inhibitory effect of the PPARbeta ligand on sPLA2 activity and prostaglandin E2 release. Thus, the inhibition of sPLA2-IIA activity by PPARbeta agonists may provide a promising approach to impacting the initiation and progression of atherosclerosis.