Group IIA secreted phospholipase A2 (PLA2G2A) augments adipose tissue thermogenesis.

Group IIA secreted phospholipase A2 (PLA2G2A) hydrolyzes glycerophospholipids at the sn-2 position resulting in the release of fatty acids and lysophospholipids. C57BL/6 mice do not express Pla2g2a due to a frameshift mutation (wild-type [WT] mice). We previously reported that transgenic expression of human PLA2G2A in C57BL/6 mice (IIA+ mice) protects against weight gain and insulin resistance, in part by increasing total energy expenditure. Additionally, we found that brown and white adipocytes from IIA+ mice have increased expression of mitochondrial uncoupling markers, such as uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor-gamma coactivator, and PR domain containing 16, suggesting that the energy expenditure phenotype might be due to an increased thermogenic capacity in adipose tissue. Here, we further characterize the impact of PLA2G2A on thermogenic mechanisms in adipose tissue. Metabolic analysis of WT and IIA+ mice revealed that even when housed within their thermoneutral zone, IIA+ mice have elevated energy expenditure compared to WT littermates. Increased energy expenditure in IIA+ mice is associated with increased citrate synthase activity in brown adipose tissue (BAT) and increased mitochondrial respiration in both brown and white adipocytes. We also observed that direct addition of recombinant PLA2G2A enzyme to in vitro cultured adipocytes results in the marked induction of UCP1 protein expression. Finally, we report that PLA2G2A induces the expression of numerous transcripts related to energy substrate transport and metabolism in BAT, suggestive of an increase in substrate flux to fuel BAT activity. These data demonstrate that PLA2G2A enhances adipose tissue thermogenesis, in part, through elevated substrate delivery and increased mitochondrial content in BAT.

PLA2G2A Phospholipase Promotes Fatty Acid Synthesis and Energy Metabolism in Pancreatic Cancer Cells with K-ras Mutation.

Oncogenic K-ras is often activated in pancreatic ductal adenocarcinoma (PDAC) due to frequent mutation (>90%), which drives multiple cellular processes, including alterations in lipid metabolism associated with a malignant phenotype. However, the role and mechanism of the altered lipid metabolism in K-ras-driven cancer remains poorly understood. In this study, using human pancreatic epithelial cells harboring inducible K-rasG12D (HPNE/K-rasG12D) and pancreatic cancer cell lines, we found that the expression of phospholipase A2 group IIA (PLA2G2A) was upregulated by oncogenic K-ras. The elevated expression of PLA2G2A was also observed in pancreatic cancer tissues and was correlated with poor survival of PDAC patients. Abrogation of PLA2G2A by siRNA or by pharmacological inhibition using tanshinone I significantly increased lipid peroxidation, reduced fatty acid synthase (FASN) expression, and impaired mitochondrial function manifested by a decrease in mitochondrial transmembrane potential and a reduction in ATP production, leading to the inhibition of cancer cell proliferation. Our study suggests that high expression of PLA2G2A induced by oncogenic K-ras promotes cancer cell survival, likely by reducing lipid peroxidation through its ability to facilitate the removal of polyunsaturated fatty acids from lipid membranes by enhancing the de novo fatty acid synthesis and energy metabolism to support cancer cell proliferation. As such, PLA2G2A might function as a downstream mediator of K-ras and could be a potential therapeutic target.

Secretory phospholipase A2 group IIA enhances the metabolic rate and increases glucose utilization in response to thyroid hormone.

Secretory phospholipase A2 group IIA (PLA2G2A) is a phospholipase which has a role in inflammation, atherogenesis, and host defense. Previously, we found that PLA2G2A protects mice on high-fat diets from weight gain and insulin resistance. Here, we examined the regulation of PLA2G2A and the metabolic changes that occur in response to variations in thyroid status. In particular, the impact of PLA2G2A on the brown adipose tissue (BAT) thermogenic gene expression was explored. We induced hypothyroidism in C57BL/6 and PLA2G2A-overexpressing (IIA+) mice over a 10 wk period or treated them with thyroid hormone (T3) for 5 wk. There were no significant changes in PLA2G2A abundance in response to thyroid status. The energy expenditure of hypothyroid IIA+ mice did not increase; however, the energy expenditure, substrate utilization, insulin sensitivity, and glucose tolerance were all elevated in the IIA+ mice given T3. Moreover, white adipocytes from IIA+ mice were much more prone to "beiging," including increased expression of brown adipose thermogenic markers such as uncoupling protein 1 (UCP1), PR domain containing 16, and early B cell factor 2. Finally, the BAT of IIA+ mice had increased UCP1 and other proteins indicative of mitochondrial uncoupling and nonshivering adaptive thermogenesis. These data reveal a novel role for PLA2G2A on adipose tissue thermogenesis depending on thyroid status.-Kuefner, M. S., Deng, X., Stephenson, E. J., Pham, K., Park, E. A. Secretory phospholipase A2 group IIA enhances the metabolic rate and increases glucose utilization in response to thyroid hormone.

Urocortin and corticotrophin-releasing hormone receptor type 2 mRNA are highly expressed in deep infiltrating endometriotic lesions.

Ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE) are the most severe forms of endometriosis, but different pathogenetic mechanisms and clinical symptoms distinguish these two forms. Corticotrophin-releasing hormone (CRH) and urocortin (Ucn) are endometrial neuropeptides involved in tissue differentiation and inflammation. The expression of CRH, Ucn, Ucn2, CRH-receptors (type-1 and type-2) and inflammatory enzymes phospholipase-A2 group IIA (PLA2G2A) and cycloxygenase-2 (COX2) were evaluated in OMA (n = 22) and DIE (n = 26). The effect of CRH or Ucn on COX2 mRNA expression was evaluated in cultured human endometrial stromal cells. In DIE lesions, CRH, Ucn and CRH-R2 mRNA levels were significantly higher than in OMA (P < 0.01, P < 0.001 and P < 0.05, respectively); DIE lesions showed a higher expression of COX2 (P < 0.01) and PLA2G2A (P < 0.05) mRNA than OMA, which was positively correlated with CRH-R2 mRNA expression (P < 0.05). Intense immunostaining for CRH and Ucn was shown in DIE. Treatment of cultured endometrial stromal cells with Ucn significantly increased COX2 mRNA expression (P < 0.01); this effect was reversed by the CRH-R2 antagonist astressin-2B. In DIE, DIE lesions highly express neuropeptide and enzyme mRNAs, supporting a strong activation of inflammatory pathways.

PLA2G2A overexpression is associated with poor therapeutic response and inferior outcome in rectal cancer patients receiving neoadjuvant concurrent chemoradiotherapy.

AIMS: The aim of this study was to investigate the prognostic impact of group IIA phospholipase A2 (PLA2G2A) expression and its role in predicting the response to neoadjuvant concurrent cheomoradiotherapy (CCRT) in rectal cancer. METHODS AND RESULTS: Through analysing a public transcriptome of rectal cancers, the PLA2G2A gene was identified as a significant predictor for CCRT response. We validated the expression of PLA2G2A using immunohistochemistry in the pretreatment tumour specimens from 172 patients with rectal cancer. The results were correlated with clinicopathological features, tumour regression grade, overall survival (OS), disease-free survival (DFS) and local recurrence-free survival (LRFS). High expression of PLA2G2A was associated with advanced pretreatment tumour status (P = 0.001), advanced pretreatment nodal status (P = 0.010), advanced post-treatment tumour status (P = 0.002) and lower tumour regression grade (P = 0.006). Furthermore, PLA2G2A expression was correlated negatively with gamma H2A histone family, member X (γ-H2AX) expression (P < 0.001, r = -0.580). More importantly, high expression of PLA2G2A emerged as an adverse prognostic factor for OS (P = 0.0190), DFS (P < 0.0001) and LRFS (P < 0.0001). In multivariate analysis, it remained independently prognostic for shorter DFS (P = 0.014) and LRFS (P = 0.012). CONCLUSIONS: High expression of PLA2G2A was associated with poor therapeutic response and worse survival in patients with rectal cancer receiving neoadjuvant CCRT, justifying PLA2G2A as an important marker to predict CCRT response and outcome.

Phospholipase A2 group IIA is elevated in endometriomas but not in peritoneal fluid and serum of ovarian endometriosis patients.

Our previous gene expression analysis identified phospholipase A2 group IIA (PLA2G2A) as a potential biomarker of ovarian endometriosis. The aim of this study was to evaluate PLA2G2A mRNA and protein levels in tissue samples (endometriomas and normal endometrium) and in serum and peritoneal fluid of ovarian endometriosis patients and control women. One-hundred and sixteen women were included in this study: the case group included 70 ovarian endometriosis patients, and the control group included 38 healthy women and 8 patients with benign ovarian cysts. We observed 41.6-fold greater PLA2G2A mRNA levels in endometrioma tissue, compared to normal endometrium tissue. Using Western blotting, PLA2G2A was detected in all samples of endometriomas, but not in normal endometrium, and immunohistochemistry showed PLA2G2A-specific staining in epithelial cells of endometrioma paraffin sections. However, there were no significant differences in PLA2G2A levels between cases and controls according to ELISA of peritoneal fluid (6.0 ± 4.4 ng/ml, 6.6 ± 4.3 ng/ml; p = 0.5240) and serum (2.9 ± 2.1 ng/ml, 3.1 ± 2.2 ng/ml; p = 0.7989). Our data indicate that PLA2G2A is implicated in the pathophysiology of ovarian endometriosis, but that it cannot be used as a diagnostic biomarker.

Thyroid hormone status regulates the expression of secretory phospholipases.

Thyroid hormone (T3) stimulates various metabolic pathways and the hepatic actions of T3 are mediated primarily through the thyroid hormone receptor beta (TRß). Hypothyroidism has been linked with low grade inflammation, elevated risk of hepatic steatosis and atherosclerosis. Secretory phospholipases (sPLA2) are associated with inflammation, hyperlipidemia and atherosclerosis. Due to potential linkage between thyroid hormone and sPLA2, we investigated the effect of thyroid hormone status on the regulation of secretory phospholipases in mice, rats and human liver. T3 suppressed the expression of the sPLA2 group IIa (PLA2g2a) gene in the liver of BALB/c mice and C57BL/6 transgenic mice expressing the human PLA2g2a. PLA2g2a was elevated with hypothyroidism and high fat diets which may contribute to the low grade inflammation associated with hypothyroidism and diet induced obesity. We also examined the effects of the TRß agonist eprotirome on hepatic gene regulation. We observed that eprotirome inhibited the expression of selected sPLA2 genes and furthermore the cytokine mediated induction PLA2g2a was suppressed. In addition, eprotirome induced genes involved in fatty acid oxidation and cholesterol clearance while inhibiting lipogenic genes. Our results indicate that in vivo thyroid hormone status regulates the abundance of sPLA2 and the inhibition of PLA2g2a by T3 is conserved across species. By regulating sPLA2 genes, T3 may impact processes associated with atherosclerosis and inflammation and TRß agonists may ameliorate inflammation and hyperlipidemia.

Integration of transcriptomics and metabolomics identify biomarkers of aberrant lipid metabolism in ulcerative colitis.

BACKGROUND: The incidence of ulcerative colitis (UC) continues to rise globally, but effective therapeutic targets are still lacking. In recent years, numerous studies have indicated that lipid therapies could offer a novel perspective for UC treatment. Given the absence of prior research utilizing high-throughput data to identify target genes associated with lipid metabolism, we conducted this work. METHODS: The training set for this study was derived from four datasets within the Gene Expression Omnibus (GEO), encompassing a total of 357 UC patients. We employed four machine learning methods (LASSO, SVM, RF, and Boruta) to jointly identify core biomarkers in these patients, whose aberrant expression needed to be validated in independent datasets and in dextrose sulfate sodium salt (DSS)-induced UC mouse models. Regarding metabolomics, we detected abnormal oxidized lipids in the serum of UC mouse using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in conjunction with orthogonal partial least squares-discriminant analysis (OPLS-DA). RESULTS: Phospholipase A2 Group IIA (PLA2G2A) was first identified as a possible biomarker for UC, with AUC values of 0.810 and 1.000 in the two validation sets, while in animal models the gene showed similarly significant up-regulation in damaged intestinal mucosa. Further analysis of this gene showed that it was positively correlated with 17 immune cell types and histological severity. Additionally, we pioneered the development of a lipid metabolism score in UC research, which outperformed all individual genes in terms of disease diagnostic efficacy (AUC values of 0.980 and 1.000 for the two validation sets, respectively). Finally, the metabolomics study also identified 31 significantly abnormal oxidized lipids, including 12-HHT and DHA. CONCLUSIONS: PLA2G2A is a key therapeutic target for UC, and oxidized lipids such as 12-HHT can serve as potential serologic indicators for diagnosis.

Phospholipase A2 enzymes PLA2G2A and PLA2G12B as potential diagnostic and prognostic biomarkers in cholangiocarcinoma.

BACKGROUND: Phospholipase A2 (PLA2) enzymes are pivotal in various biological processes, such as lipid mediator production, membrane remodeling, bioenergetics, and maintaining the body surface barrier. Notably, these enzymes play a significant role in the development of diverse tumors. AIM: To systematically and comprehensively explore the expression of the PLA2 family genes and their potential implications in cholangiocarcinoma (CCA). METHODS: We conducted an analysis of five CCA datasets from The Cancer Genome Atlas and the Gene Expression Omnibus. The study identified differentially expressed genes between tumor tissues and adjacent normal tissues, with a focus on PLA2G2A and PLA2G12B. Gene Set Enrichment Analysis was utilized to pinpoint associated pathways. Moreover, relevant hub genes and microRNAs for PLA2G2A and PLA2G12B were predicted, and their correlation with the prognosis of CCA was evaluated. RESULTS: PLA2G2A and PLA2G12B were discerned as differentially expressed in CCA, manifesting significant variations in expression levels in urine and serum between CCA patients and healthy individuals. Elevated expression of PLA2G2A was correlated with poorer overall survival in CCA patients. Additionally, the study delineated pathways and miRNAs associated with these genes. CONCLUSION: Our findings suggest that PLA2G2A and PLA2G12B may serve as novel potential diagnostic and prognostic markers for CCA. The increased levels of these genes in biological fluids could be employed as non-invasive markers for CCA, and their expression levels are indicative of prognosis, underscoring their potential utility in clinical settings.

Proteomic profiling and functional characterization of serum-derived extracellular vesicles in the mucinous and non-mucinous colon adenocarcinoma.

PURPOSE: Mucinous adenocarcinoma (MC) is a distinct pathological subtype of colon adenocarcinoma, which is associated with a worse prognosis compared with non-mucinous adenocarcinoma (AC). However, clear distinctions between MC and AC remain unknown. Extracellular vesicles (EVs) are a class of enclosed vesicles containing proteins, lipids, and nucleic acids that are secreted by cells into surrounding tissues or into serum. The EVs could facilitate tumorigenesis by regulating tumor cell proliferation, invasiveness, metastasis, angiogenesis, and evasion of immune surveillance. METHODS: Quantitative proteomics analysis was performed to determine the characterization and biological differences of serum-derived EVs in two subtypes of colon adenocarcinoma (MC and AC). Serum-derived EVs from patients with MC, AC, and healthy volunteers were included in this study. The role of PLA2G2A in cell migration and invasion were evaluate with transwell assay, and its prognostic predictive value was further assessed based on TCGA database. RESULTS: Quantitative proteomics analysis revealed 846 differentially expressed proteins (DEPs) in EVs from MC patients compared with those from AC patients. Bioinformatics analysis revealed that the most prominent protein cluster included those involved in cell migration and the tumor microenvironment. Overexpression of PLA2G2A, one of the key EV proteins upregulated in patients with MC, in colon cancer cell line SW480 promoted the cell invasion and migration ability. In addition, the high level of PLA2G2A is associated with poor prognosis of colon cancer patients harboring BRAF mutations. Further, after EV stimulation, proteomic analysis of recipient SW480 cells showed that MC-derived EVs activated multiple cancer-related pathways, including the Wnt/ß-Catenin signaling pathway, and might promote the malignancy of mucinous adenocarcinoma through these pathways. CONCLUSIONS: The identification of differential protein profiles between MC and AC helps to elucidate the underlying molecular mechanisms of MC pathogenesis. The PLA2G2A in EVs is a potential prognostic predictive marker for those patients harboring with BRAF mutations.

Identification and immunological characterization of PLA2G2A and cell death-associated molecular clusters in idiopathic pulmonary fibrosis.

AIMS: Idiopathic pulmonary fibrosis (IPF) is a severe pulmonary interstitial pneumonia. Our study focuses on the role of PLA2 enzyme in the IPF to explore a more effective diagnosis and treatment mechanism of IPF. MAIN METHODS: Transcriptome data of IPF from GEO database and bleomycin-induced pulmonary fibrosis mice were analyzed to identify PLA2 enzyme and their metabolite, lysophosphatidylcholines 18:0, in IPF. Based on PLA2G2A and PLA2G2D / PLA2G2A-associated cell death genes (PCDs), the consensus clustering analysis was used to identify the subtypes of IPF and the correlation between PLA2G2A and prognosis was analyzed. The machine learning (ML) models and artificial neural network (ANN) model was used to validate the diagnostic accuracy of PLA2s and PCDs in diagnosing IPF. The gene and protein expression of NLRP3, GSDMD, and CASP-1 was estimated in recombinant PLA2G2A protein induced MLE-12 cells. KEY FINDINGS: The expression of PLA2G2D, PLA2G2A, and LPC18 significantly changed in IPF. Furtherly, PLA2G2A has a significant correlation with poor patient prognosis, which could predict the 2 or 3-years mortality rates of IPF. Two subtypes of IPF patients, identified based on PCDs, showed significant different immunoinfiltration. Recombinant PLA2G2A protein could induce the pyrotosis in the MLE-12 cell. The generalized linear model and ANN model of PLA2s or PCDs accurate diagnosis IPF. SIGNIFICANCE: PLA2G2A is the most robustly associated gene with IPF among the PLA2s, which demonstrates a potential in diagnosing and prognostic value in IPF, and provides a foundation for further understanding and breakthroughs in IPF diagnosis and treatment.

Phospholipase A2 Group IIA Is Associated with Inflammatory Hepatocellular Adenoma.

Although benign hepatocellular adenomas (HCA) are very rare, recent observations have shown their occurrence in patients with diabetes mellitus. Consequently, most of these cases are treated by resection due to concerns regarding their potential progression to hepatocarcinoma (HCC). This decision is largely driven by the limited number of studies on HCC subtyping and the lack of molecular and biological insights into the carcinogenic potential of benign tumors. This study aimed to comprehensively investigate the subtype classification of HCA and to compare and analyze gene expression profiling between HCA and HCC tissues. One fresh inflammatory HCA (I-HCA), three non-B non-C HCCs, two hepatitis B virus-HCCs, and one normal liver tissue sample were subjected to single-cell RNA sequencing (scRNA-seq). Comparative analysis of scRNA-seq among different tissues showed that phospholipase A2 group IIA (PLA2G2A) mRNA was specifically expressed in I-HCA, following RNA-seq analysis in formalin-fixed paraffin-embedded tissues from other HCAs. Immunohistochemistry using the PLA2G2A antibody in these tissues indicated that the positive reaction was mainly observed in hepatocytes of I-HCAs and stromal cells surrounding the tumor tissue in HCC were also stained. According to a clinical database, PLA2G2A expression in HCC does not correlate with poor prognosis. This finding may potentially help develop a new definition for I-HCA, resulting in a significant clinical contribution, but it requires validation with other fresh HCA samples.

PLA2G2A+ cancer-associated fibroblasts mediate pancreatic cancer immune escape via impeding antitumor immune response of CD8+ cytotoxic T cells.

Our previous research defined a novel metabolic cancer associated fibroblasts subset (meCAFs) enriched in loose-type pancreatic ductal adenocarcinoma (PDAC) and related to CD8+ T cells accumulation. Consistently, the abundance of meCAFs was associated with poor prognosis but better immunotherapy responses in PDAC patients. However, the metabolic characteristic of meCAFs and its cross-talk with CD8+ T cells remain to be elucidated. In this study, we identified PLA2G2A as a marker of meCAFs. In particular, the abundance of PLA2G2A+ meCAFs was positively related to the accumulation of total CD8+ T cells and negatively correlated with clinical outcomes of PDAC patients and infiltration of intratumoral CD8+ T cells. We demonstrated that PLA2G2A+ meCAFs substantially attenuated the antitumor ability of tumor infiltrating CD8+ T cells and facilitated tumor immune escape in PDAC. Mechanistically, PLA2G2A regulated the function of CD8+ T cells as a pivotal soluble mediator via MAPK/Erk and NF-κB signaling pathways. In conclusion, our study identified the unrecognized role of PLA2G2A+ meCAFs in promoting tumor immune escape by impeding the antitumor immune function of CD8+ T cells, and strongly suggested PLA2G2A as a promising biomarker and therapeutic target for immunotherapy in PDAC.

COVID-19, Blood Lipid Changes, and Thrombosis.

Although there is increasing evidence that oxidative stress and inflammation induced by COVID-19 may contribute to increased risk and severity of thromboses, the underlying mechanism(s) remain to be understood. The purpose of this review is to highlight the role of blood lipids in association with thrombosis events observed in COVID-19 patients. Among different types of phospholipases A2 that target cell membrane phospholipids, there is increasing focus on the inflammatory secretory phospholipase A2 IIA (sPLA2-IIA), which is associated with the severity of COVID-19. Analysis indicates increased sPLA2-IIA levels together with eicosanoids in the sera of COVID patients. sPLA2 could metabolise phospholipids in platelets, erythrocytes, and endothelial cells to produce arachidonic acid (ARA) and lysophospholipids. Arachidonic acid in platelets is metabolised to prostaglandin H2 and thromboxane A2, known for their pro-coagulation and vasoconstrictive properties. Lysophospholipids, such as lysophosphatidylcholine, could be metabolised by autotaxin (ATX) and further converted to lysophosphatidic acid (LPA). Increased ATX has been found in the serum of patients with COVID-19, and LPA has recently been found to induce NETosis, a clotting mechanism triggered by the release of extracellular fibres from neutrophils and a key feature of the COVID-19 hypercoagulable state. PLA2 could also catalyse the formation of platelet activating factor (PAF) from membrane ether phospholipids. Many of the above lipid mediators are increased in the blood of patients with COVID-19. Together, findings from analyses of blood lipids in COVID-19 patients suggest an important role for metabolites of sPLA2-IIA in COVID-19-associated coagulopathy (CAC).

Effect of copy number variation of PLA2G2A gene to growth traits in Chinese cattle.

SIMPLE SUMMARY: As a member of genetic polymorphism, copy number variation has been a commonly used method in the world for investigating effect of genetic polymorphism on gene expression. Effect of genetic polymorphism made on livestock development has been more and more important in beef cattle molecular breeding. The characteristics of Chinese cattle are excellent meat quality, tolerant to rough feeding, good environmental adaptability and so on. But there are some obvious weaknesses still exist in the process of cattle growth and development, such as weak hindquarters and growth slowly. To improve the growth performance and market competitiveness of Chinese cattle, a lot of studies have been made about finding and investigating effective molecular marker. In this study, Q-PCR and data association analysis were used for PLA2G2A gene copy number variation detection and related effect analysis in Chinese cattle. Results showed that PLA2G2A gene has a significant effect on two breeds of Chinese cattle on growth traits, which could be a basic materials and effective information of cattle molecular markers breeding. PLA2G2A, member of secreted phospholipases A2 (sPLA2) in superfamily of phospholipase A2, could catalyze the process of glycerophospholipids hydrolysis from position of sn-2 acyl with the release of free fatty acids and lysophospholipids. Researches about PLA2G2A gene are mostly focus on disease, including tumors and diabetes, the number of study occurred on animal breeding is weak. In this study, blood samples were collected from five breeds of Chinese cattle (Qingchuan cattle, Xianan cattle, Yunling cattle, Pinan cattle and Guyuan cattle) for PLA2G2A gene CNV type detection. SPSS 20.0 software and method of ANOVA were used to analyzed the association between types of CNV and growth traits. Results reveal that the distribution of different copy number types in different cattle breeds is different. In QC, XN and GY cattle, the frequencies of Deletion and Duplication are about 40%; in YL cattle, the frequency of Deletion type exceeds 60%; in PN cattle, the frequency of Duplication is closed to 80%. Association analysis indicate that CNV of PLA2G2A gene showed a positive effect in cattle growth: in QC cattle, Chest depth with Normal type copy number possess a increased trend (P < 0.05); individuals with Deletion type copy number have better performance on Height at sacrum, Heart girth and Body height in GY cattle (P < 0.05). The functional role and molecular mechanism of PLA2G2A gene in animal growth and development are still unclear, and it is necessary for processing a further research. This research aims to provide basic materials for molecular breeding of Chinese cattle.

Clinical Significance of PLA2G2A Expression in Gastric Cancer Patients who Receive Gastrectomy and Adjuvant S-1.

BACKGROUND/AIM: This study aimed to evaluate the prognostic significance of PLA2G2A expression in patients with locally advanced gastric cancer (GC). PATIENTS AND METHODS: PLA2G2A expression levels in cancerous tissue specimens and adjacent normal mucosa obtained from 134 patients with stage II/III GC who received adjuvant chemotherapy with S-1 after curative resection were measured using real-time quantitative polymerase chain reaction. Subsequently, the associations of PLA2G2A expression with clinicopathological features and survival were evaluated. RESULTS: No association was observed between clinicopathological features and PLA2G2A expression levels. Overall survival was significantly longer in patients with high PLA2G2A expression levels (p=0.022). Multivariate analysis revealed that PLA2G2A expression was a significant, independent prognostic factor (hazard ratio=0.136; 95% confidence interval=0.0185-0.992; p=0.049). CONCLUSION: PLA2G2A mRNA expression may serve as a useful prognostic marker in patients with locally advanced GC who receive curative surgery and adjuvant chemotherapy with S-1.

Short Linear Motifs Characterizing Snake Venom and Mammalian Phospholipases A2.

Snake venom phospholipases A2 (PLA2s) have sequences and structures very similar to those of mammalian group I and II secretory PLA2s, but they possess many toxic properties, ranging from the inhibition of coagulation to the blockage of nerve transmission, and the induction of muscle necrosis. The biological properties of these proteins are not only due to their enzymatic activity, but also to protein-protein interactions which are still unidentified. Here, we compare sequence alignments of snake venom and mammalian PLA2s, grouped according to their structure and biological activity, looking for differences that can justify their different behavior. This bioinformatics analysis has evidenced three distinct regions, two central and one C-terminal, having amino acid compositions that distinguish the different categories of PLA2s. In these regions, we identified short linear motifs (SLiMs), peptide modules involved in protein-protein interactions, conserved in mammalian and not in snake venom PLA2s, or vice versa. The different content in the SLiMs of snake venom with respect to mammalian PLA2s may result in the formation of protein membrane complexes having a toxic activity, or in the formation of complexes whose activity cannot be blocked due to the lack of switches in the toxic PLA2s, as the motif recognized by the prolyl isomerase Pin1.

Association of 5'UTR polymorphism of secretory phospholipase A2 group IIA (PLA2G2A) gene with prostate cancer metastasis.

Phospholipase A2 (PLA2) enzymes are small lipolytic hydrolases that can regulate immune responses through generation of Arachidonic Acid (AA), a precursor molecule of lipid mediators like prostaglandins, leukotrienes and thromboxanes. One of the family members of PLA2, secretory Phospholipase A2 Group IIA (PLA2G2A), was associated with different types of malignancies including prostate cancer. Elevated serum levels of PLA2G2A was found in prostate cancer (PCa) patients and associated with increased tumor grade in literature. 5'UTR regions have regulatory role in protein expression by controlling the accessibility of factors necessary for the translation initiation. Single nucleotide polymorphisms at 5'UTR regions have the potential to affect mRNA translation efficiency resulting in altered protein levels depending on structure and nucleotide content. Given that the 5'UTR polymorphism in PLA2G2A gene (rs11573156) is associated with increased serum levels of PLA2G2A, the association of this 5'UTR polymorphism with PCa susceptibility and metastasis was investigated in this study. Total of 261 PCa patients and 128 control individuals were genotyped with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Individuals with heterozygous CG genotype was found to have significantly reduced risk of PCa metastasis with an Odds Ratio (OR) of 0.405 (p = 0.028, 95%CI = 0.181-0.906), compared to the carriers of homozygous CC genotype (p > 0.05) suggesting an anti-metastatic effect for the G allele. No association was found between PCa susceptibility and Gleason score (p > 0.05) in Turkish population.

In silico investigation of the molecular effects caused by R123H variant in secretory phospholipase A2-IIA associated with ARDS.

Phospholipase A2-IIA catalyzes the hydrolysis of the sn-2 ester of glycerophospholipids. A rare c.428G > A (p.Arg143His) variant in PLA2G2A gene was found in two infants affected by acute respiratory distress syndrome (ARDS) by whole coding region and exon/intron boundaries sequencing. To obtain insights into the possible molecular effects of the rare R123H mutation in secretory PLA2-IIA (sPLA2-IIA), molecular modelling, molecular dynamics (MD) using principal component analysis (PCA) and continuum electrostatic calculations were conducted on the crystal structure of the wild type protein and on a generated model structure of the R123H mutant. Analysis of MD trajectories indicate that the overall stability of the protein is not affected by this mutation but nevertheless the catalytically crucial H-bond between Tyr51 and Asp91 as well as main electrostatic interactions in the region close to the mutation site are altered. PCA results indicate that the R123H replacement alter the internal molecular motions of the enzyme and that collective motions are increased. Electrostatic surface potential studies suggest that after mutation the interfacial binding to anionic phospholipid membranes and anionic proteins may be changed. The strengthening of electrostatic interactions may be propagated into the active site region thus potentially affecting the substrate recognition and enzymatic activity. Our findings provide the basis for further investigation and advances our understanding of the effects of mutations on sPLA2 structure and function.

The 763C>G Polymorphism of The Secretory PLA2IIa Gene Is Associated with Endometriosis in Iranian Women.

BACKGROUND: Endometriosis is a chronic gynecological disease resulting from complex interactions between genetic, hormonal, environmental and oxidative stress and intrinsic inflammatory components. The aim of this study was to investigate the potential association of the 763C>G polymorphism in the secretory phospholipase A2 group IIa gene (PLA2G2A) with the risk of endometriosis in Iranian women. MATERIALS AND METHODS: Ninety seven patients with endometriosis along with 107 women who were negative for endometriosis after laparoscopy and laparatomy, and served as the control group, were enrolled for this cross-sectional study. Samples were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: Multivariate analysis was used to examine the association between the risk of endometriosis and the 763C>G polymorphism of PLA2G2A. Genotype distributions of PLA2G2A were significantly different between patients and the controls (p<0.001, OR=0.22, 95% CI=0.21-0.39). Correlation analysis showed that there was a significant association between the normal homozygous genotype and susceptibility to endometriosis (p<0.001). CONCLUSION: The present study suggests that the 763C>G polymorphism of PLA2G2A plays an important role as an independent factor in the risk of endometriosis in Iranian women.