PLA2G7 Human

What is the molecular structure and function of PLA2G7 in human cells?

PLA2G7 is encoded by a gene located on chromosome 6 in humans and functions as a phospholipase that hydrolyzes oxidized phospholipids . The enzyme plays critical roles in phospholipid metabolism and inflammatory processes. Methodologically, researchers investigate PLA2G7 structure through X-ray crystallography and its enzymatic activity through specialized assays measuring hydrolysis of specific phospholipid substrates. The protein's catalytic domain contains a lipase consensus sequence that is essential for its phospholipase activity.

What cellular pathways regulate PLA2G7 expression in human tissues?

PLA2G7 expression is regulated through multiple signaling pathways including inflammatory cytokine cascades and lipid metabolism networks. Methodologically, researchers study these regulatory mechanisms using reporter gene assays, chromatin immunoprecipitation, and pathway inhibition approaches. In macrophages particularly, PLA2G7 expression can be induced by inflammatory stimuli, suggesting interconnection with immune response pathways. Experimental designs typically involve treating cells with pathway activators or inhibitors followed by measurement of PLA2G7 expression via quantitative PCR or Western blotting.

How does PLA2G7 expression differ across human tissue types?

PLA2G7 demonstrates tissue-specific expression patterns, with notable expression in immune cells, particularly macrophages, as well as in certain cancer tissues. Methodologically, researchers examine tissue-specific expression using RNA-seq, immunohistochemistry, and tissue microarrays. Single-cell RNA sequencing analyses have revealed predominant PLA2G7 expression in intratumoral macrophages within the hepatocellular carcinoma microenvironment . In prostate cancer, PLA2G7 serves as a cancer-selective biomarker in approximately 50% of cases .

What mechanisms underlie PLA2G7's promotion of cancer cell migration and invasion?

PLA2G7 promotes cancer progression through multiple mechanisms affecting cell proliferation, apoptosis, and migration. In prostate cancer, PLA2G7 silencing studies have demonstrated anti-proliferative, pro-apoptotic, and anti-migratorial effects, suggesting this enzyme normally supports tumor cell survival and invasion . Methodologically, researchers investigate these mechanisms using wound healing assays, transwell migration assays, and invasion assays with matrix barriers. In diffuse large B-cell lymphoma (DLBCL), knockdown of PLA2G7 suppressed tumor cell migration and colony formation while enhancing apoptotic death, providing clear evidence of its oncogenic role .

How does PLA2G7 expression correlate with cancer prognosis?

PLA2G7 expression has been associated with aggressive disease and poorer prognosis across multiple cancer types. In prostate cancer, it is linked to more aggressive disease . In hepatocellular carcinoma, macrophage-specific PLA2G7 expression significantly correlates with poorer outcomes and resistance to immunotherapy . Methodologically, researchers establish these correlations through large-scale patient cohort studies using immunohistochemistry, gene expression profiling, and detailed clinical outcomes analysis. For example, one study examined PLA2G7 expression in 1,137 prostate cancer specimens and 409 adjacent non-malignant tissues to validate its association with disease progression .

What is the relationship between PLA2G7 and ERG oncogene in prostate cancer?

PLA2G7 has been identified as a potential drug target particularly in ERG oncogene-positive prostate cancers . Methodologically, researchers investigate this relationship through co-expression analysis in patient samples and mechanistic studies in cell lines with different ERG status. Experimental approaches include stratification of prostate cancer samples by ERG status followed by PLA2G7 expression analysis, and chromatin immunoprecipitation to determine if ERG directly regulates PLA2G7 transcription. This relationship suggests potential co-regulatory mechanisms that could be exploited therapeutically.

What in vitro techniques are most effective for studying PLA2G7 function?

Effective in vitro techniques include RNA interference approaches using siRNA for PLA2G7 knockdown, as demonstrated in both DLBCL and prostate cancer cell lines . Functional assays include migration assays, colony formation assays, and apoptosis measurements (e.g., Annexin V/7AA-D staining). Methodologically, researchers confirm successful knockdown via qRT-PCR before assessing phenotypic changes. Lipidomic and gene expression profiling after PLA2G7 silencing can reveal downstream molecular alterations. For example, in DLBCL research, two different siRNA constructs were used to confirm knockdown efficiency and functional effects in DB and SU-DHL-2 cell lines .

How can PLA2G7 activity be measured in clinical samples?

PLA2G7 expression and activity in clinical samples can be assessed through multiple techniques. Immunohistochemistry and immunofluorescence have been successfully employed in large-scale studies of prostate cancer and HCC patients . Enzyme activity assays using specific substrates allow quantification of PLA2G7 catalytic function. Methodologically, researchers develop standardized staining protocols with appropriate antibody validation and quantification methods (H-score or digital image analysis). For higher throughput, tissue microarrays enable simultaneous analysis of multiple patient samples. RNA-based methods include qRT-PCR and RNA sequencing for gene expression analysis.

What animal models are optimal for investigating PLA2G7 in cancer?

Both orthotopic and subcutaneous mouse models have been employed to evaluate PLA2G7's role in cancer progression and response to therapy. For studying PLA2G7 in the context of immunotherapy, orthotopic and subcutaneous HCC mouse models have proven valuable for evaluating the PLA2G7 inhibitor darapladib in combination with immune checkpoint blockade therapy . Methodologically, researchers typically use immunocompromised mice for human xenograft studies or genetically engineered mouse models that recapitulate specific cancer types. For investigating interactions with the immune system, syngeneic mouse models with intact immune systems are preferable.

How does PLA2G7 influence tumor-associated macrophage function?

PLA2G7 expression in macrophages contributes to their immunosuppressive phenotype within the tumor microenvironment. In HCC, single-cell RNA sequencing analyses have revealed that PLA2G7-high macrophages represent a highly immunosuppressive subset that impedes CD8 T-cell activation . Methodologically, researchers investigate these functions through flow cytometry and in vitro co-culture systems that elucidate specific interactions between macrophages and T cells. The enzyme's role in lipid metabolism likely influences immune cell function through production of bioactive lipid mediators, which can be characterized through targeted lipidomics.

How does macrophage-specific PLA2G7 affect immunotherapy response?

In HCC, macrophage-specific PLA2G7 expression correlates significantly with immunotherapy resistance . This suggests PLA2G7 contributes to an immunosuppressive tumor microenvironment that limits the efficacy of checkpoint inhibitors. Methodologically, researchers assess this relationship through immunohistochemistry and immunofluorescence in patient samples correlated with treatment outcomes. Experimental models include flow cytometric analysis of tumor-infiltrating lymphocytes and functional assays of T cell activity. The finding that pharmacological inhibition of PLA2G7 improves anti-PD-1 efficacy in mouse models provides mechanistic support for this relationship .

What cell types express PLA2G7 in the tumor microenvironment?

While PLA2G7 can be expressed by tumor cells themselves, as seen in prostate cancer and DLBCL , recent research has highlighted its predominant expression in intratumoral macrophages within certain cancer types like HCC . Methodologically, researchers determine cell type-specific expression through single-cell RNA sequencing, immunohistochemistry with dual staining, and flow cytometry with cell sorting. This cell type-specific expression pattern suggests different therapeutic implications depending on the cancer type and predominant cellular source of PLA2G7.

What pharmacological inhibitors of PLA2G7 are available for research?

The primary pharmacological inhibitor used in research settings is darapladib, which has been employed to target PLA2G7 in HCC mouse models . Methodologically, researchers administer darapladib in various formulations, dosages, and schedules to optimize inhibition while minimizing toxicity. In vitro dose-response studies typically precede in vivo applications. Complementary genetic approaches using RNA interference (siRNA, shRNA) provide validation of pharmacological findings and help distinguish on-target from off-target effects.

How does combining PLA2G7 inhibition with statins affect cancer cells?

The anti-proliferative effect of PLA2G7 silencing is potentiated by lipid-lowering statins in prostate cancer cells, suggesting synergistic activity . Methodologically, researchers conduct combination studies using matrix experimental designs with varying concentrations of each agent to identify optimal combinations and detect synergy. This combination represents a potential therapeutic approach through repurposing statins, which are already clinically approved drugs with established safety profiles, providing a rationale for combining PLA2G7 inhibition with statins in prostate cancer management .

What evidence supports PLA2G7 inhibition for enhancing immunotherapy?

In HCC mouse models, pharmacological inhibition of PLA2G7 by darapladib improved the therapeutic efficacy of anti-PD-1 antibodies . Methodologically, researchers conduct controlled animal studies comparing single-agent treatments with combination therapy, measuring tumor growth, survival, and immune parameters. Flow cytometric analysis of tumor-infiltrating lymphocytes and cytokine profiling help elucidate mechanisms. These findings support the concept that PLA2G7 inhibition can enhance immunotherapy by reversing the immunosuppressive function of intratumoral macrophages, providing a rationale for clinical investigation of this combination .

What mechanisms explain differential effects of PLA2G7 across cancer types?

The differential effects of PLA2G7 inhibition across cancer types likely reflect tissue-specific contexts, varying roles in different tumor microenvironments, and cancer-specific molecular alterations. In prostate cancer, PLA2G7 appears directly linked to cancer cell migration and invasion , while in HCC, its effects are primarily mediated through macrophage immunosuppressive functions . In DLBCL, PLA2G7 promotes tumor cell proliferation and survival while inhibiting apoptosis . Methodologically, researchers investigate these differences through comparative studies across multiple cancer models and comprehensive multi-omics profiling to identify context-specific mechanisms.

How does PLA2G7 remodel the tumor microenvironment at the molecular level?

PLA2G7 likely influences the tumor microenvironment through its enzymatic activity, generating bioactive lipid mediators that affect various cell types. Its expression in macrophages promotes an immunosuppressive phenotype that impedes CD8 T-cell activation . Methodologically, researchers investigate these effects through spatial transcriptomics, multiplexed immunofluorescence imaging, and single-cell profiling to map cellular interactions. In vitro co-culture systems and in vivo models with cell-type-specific PLA2G7 manipulation help delineate causal relationships between PLA2G7 expression and immune cell function.

What is the relationship between PLA2G7, caloric restriction, and cardiovascular aging?

Research has investigated connections between PLA2G7, caloric restriction, and cardiovascular aging , though detailed molecular mechanisms require further elucidation. Methodologically, researchers study these relationships through animal models of caloric restriction, molecular profiling of cardiovascular tissues at different ages, and correlation with PLA2G7 expression and activity. The enzyme's role in lipid metabolism suggests it may influence age-related changes in vascular function, inflammation, and atherosclerosis development. Understanding how PLA2G7 functions in these pathways could reveal novel targets for mimicking caloric restriction benefits on cardiovascular health.

How might single-cell technologies advance PLA2G7 research?

Single-cell RNA sequencing has already revealed important insights about PLA2G7 expression in specific cell populations, particularly intratumoral macrophages in HCC . Methodologically, this approach can be extended to other cancer types and combined with spatial transcriptomics to understand PLA2G7 expression in the context of tissue architecture. Single-cell proteomics and metabolomics could further elucidate the functional consequences of PLA2G7 activity at the cellular level, potentially identifying new regulatory mechanisms and downstream effectors.

What biomarker strategies could optimize patient selection for PLA2G7-targeted therapies?

Given PLA2G7's differential expression and functions across cancer types, patient selection biomarkers will be critical for clinical development of PLA2G7 inhibitors. Methodologically, researchers could develop multiplex immunohistochemistry assays that simultaneously detect PLA2G7 expression and relevant cell type markers. Liquid biopsy approaches measuring circulating PLA2G7 or its metabolic products might provide less invasive monitoring. Developing predictive biomarker signatures that combine PLA2G7 status with other relevant markers (e.g., ERG status in prostate cancer or immune cell profiles in HCC ) could improve patient stratification for clinical trials.