Targeting CYP2J2 to Enhance the Anti-Glioma Efficacy of Cannabinoid Receptor 2 Stimulation by Inhibiting the Pro-Angiogenesis Function of M2 Microglia

Lei, Xuejiao; Chen, Xuezhu; Quan, Yulian; Tao, Yihao; Li, Junlong

doi:10.3389/fonc.2020.574277

Cited by 16 publications

(16 citation statements)

References 42 publications

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“…For example, overexpression of CYP2J2 is beneficial in the treatment of diabetes [10] and in the reduction of cardiac hypertrophy 12 BioMed Research International [27]. However, CYP2J2 is significantly expressed in various tumors [28,29], including KIRC, but it remains unknown if CYP2J2 overexpression in KIRC is beneficial or harmful. Therefore, we investigated the correlation between CYP2J2 expression and KIRC using various databases, including Oncomine, GEPIA DriverDBv3, and TIMER databases.…”

Section: Discussionmentioning

confidence: 99%

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CYP2J2 Is a Diagnostic and Prognostic Biomarker Associated with Immune Infiltration in Kidney Renal Clear Cell Carcinoma

Zou

2021

BioMed Research International

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Cytochrome P450 family 2 subfamily J member 2 (CYP2J2), a member of the monooxygenase cytochrome P450 (CYP) family and the only member of the human CYP2J subfamily, has many functions, including regulation of oxidative stress, inflammation, apoptosis, and immune responses. However, its role in cancer development has not been clearly elucidated. In this study, expression levels of CYP2J2 in various cancer types were determined using the Oncomine, the Gene Expression Profiling Interactive Analysis (GEIPA), DriverDBv3, UALCAN, and Tumor Immune Estimation Resource (TIMER) databases. The prognostic value of CYP2J2 for KIRC was analyzed using GEPIA, UALCAN, OSkirc, and DriverDBv3 databases. We evaluated the expression levels of CYP2J2 transcript, protein, and promoter methylation at different clinical characteristics in KIRC through the UALCAN database. Simultaneously, CYP2J2 network-related functions were evaluated using the GeneMANIA interactive tool while the biological processes involved in CYP2J2 and its interactive genes were investigated through Metascape and FunRich. Then, we used TIMER to determine the correlation between CYP2J2 expression levels and immune infiltration levels in KIRC. In KIRC, the CYP2J2 gene, RNA, and protein were found to be overexpressed. However, the methylation level of CYP2J2 promoter in KIRC was lower than in normal tissues. Surprisingly, elevated expression levels of CYP2J2 exhibited better prognostic outcomes in KIRC. Evaluation of protein-protein interaction networks and biological processes revealed that CYP2J2 was principally involved in immune responses, apoptosis, and other metabolic processes. Moreover, we found that the expression levels of CYP2J2 were positively correlated with infiltration levels of B cells, CD8 + T cells, neutrophils, and dendritic cells in KIRC. Therefore, we speculated that the overexpression of CYP2J2 prolonged the survival outcome of KIRC patients, which may be related to the change of tumor immune microenvironment. Moreover, all these new understandings of CYP2J2 may provide important value for the early diagnosis and new targeted drug therapy of KIRC.

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Section: Discussionmentioning

confidence: 99%

“…For example, overexpression of CYP2J2 is beneficial in the treatment of diabetes [ 10 ] and in the reduction of cardiac hypertrophy [ 27 ]. However, CYP2J2 is significantly expressed in various tumors [ 28 , 29 ], including KIRC, but it remains unknown if CYP2J2 overexpression in KIRC is beneficial or harmful.…”

Section: Discussionmentioning

confidence: 99%

CYP2J2 Is a Diagnostic and Prognostic Biomarker Associated with Immune Infiltration in Kidney Renal Clear Cell Carcinoma

Zou

2021

BioMed Research International

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“…Here, we detect an increase in angiogenesis and a decrease in MBP loss at 14 days after cerebral ischemia in the ADSC-EVs treated group compared to the PBS control. It is well established that M2 microglia promote angiogenesis [52,53]. For instance, culture supernatant of M2 microglia promotes angiogenesis in vitro in human brain microvassal endothelial cells (HBMECs) [50].…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles from Adipose-derived Stem Cells Promote Microglia M2 Polarization and Neurological Recovery after Ischemic Stroke

Pan

et al. 2021

Preprint

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Background: Adipose-derived stem cells (ADSCs) and their extracellular vesicles (EVs) have therapeutic potential in ischemic brain injury, but the underlying mechanism is poorly understood. The current study aimed to explore the contribution of miRNAs in ADSC-EVs to the treatment of cerebral ischemia. Methods: After the intravenous injection of ADSC-EVs, therapeutic efficacy was evaluated by neurobehavioral tests and brain atrophy volume. The polarization of microglia was assessed by immunostaining and qPCR. We further performed miRNA sequencing of ADSC-EVs and analyzed the relationship between the upregulated miRNAs in ADSC-EVs and microglial polarization-related proteins using Ingenuity Pathway Analysis (IPA). Results: The results showed that ADSC-EVs reduced brain atrophy volume, improved neuromotor and cognitive functions after mouse ischemic stroke. The loss of oligodendrocytes was attenuated after ADSC-EVs injection. The number of blood vessels, as well as newly proliferated endothelial cells in the peri-ischemia area were higher in the ADSC-EVs treated group than that in the PBS group. In addition, ADSC-EVs regulated the polarization of microglia, resulting in increased repair-promoting M2 phenotype and decreased pro-inflammatory M1 phenotype. Finally, STAT1 and PTEN were highlighted as two downstream targets of up-regulated miRNAs in ADSC-EVs among 85 microglia/macrophage polarization related proteins by IPA. The inhibition of STAT1 and PTEN by ADSC-EVs were confirmed in cultured microglia. Conclusions: In summary, ADSC-EVs reduced ischemic brain injury, which was associated with the regulation of microglial polarization. miRNAs in ADSC-EVs contributed to their function in regulating microglial polarization by targeting PTEN and STAT1.

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“…Accordingly, THC induced the profile of Th2 polarisation, resulting in an increase in Th2-associated cytokines and a downregulation of Th1-related cytokines [160]. Finally, another investigation showed that the CB 2 receptor-activating effect of cannabinoids attenuates its own antitumour effect by promoting M2 polarisation of microglia/tumour-associated macrophages (TAMs), causing a proangiogenic effect of M2 microglia [161].…”

Section: Effect Of Cannabinoid Compounds On Tumour-immune Interactionsmentioning

confidence: 99%

The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies

Ramer

Wittig

Hinz

2021

Cancers

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Despite the long history of cannabinoid use for medicinal and ritual purposes, an endogenous system of cannabinoid-controlled receptors, as well as their ligands and the enzymes that synthesise and degrade them, was only discovered in the 1990s. Since then, the endocannabinoid system has attracted widespread scientific interest regarding new pharmacological targets in cancer treatment among other reasons. Meanwhile, extensive preclinical studies have shown that cannabinoids have an inhibitory effect on tumour cell proliferation, tumour invasion, metastasis, angiogenesis, chemoresistance and epithelial-mesenchymal transition (EMT) and induce tumour cell apoptosis and autophagy as well as immune response. Appropriate cannabinoid compounds could moreover be useful for cancer patients as potential combination partners with other chemotherapeutic agents to increase their efficacy while reducing unwanted side effects. In addition to the direct activation of cannabinoid receptors through the exogenous application of corresponding agonists, another strategy is to activate these receptors by increasing the endocannabinoid levels at the corresponding pathological hotspots. Indeed, a number of studies accordingly showed an inhibitory effect of blockers of the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on tumour development and spread. This review summarises the relevant preclinical studies with FAAH and MAGL inhibitors compared to studies with cannabinoids and provides an overview of the regulation of the endocannabinoid system in cancer.

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Targeting CYP2J2 to Enhance the Anti-Glioma Efficacy of Cannabinoid Receptor 2 Stimulation by Inhibiting the Pro-Angiogenesis Function of M2 Microglia

Cited by 16 publications

References 42 publications

CYP2J2 Is a Diagnostic and Prognostic Biomarker Associated with Immune Infiltration in Kidney Renal Clear Cell Carcinoma

CYP2J2 Is a Diagnostic and Prognostic Biomarker Associated with Immune Infiltration in Kidney Renal Clear Cell Carcinoma

Extracellular Vesicles from Adipose-derived Stem Cells Promote Microglia M2 Polarization and Neurological Recovery after Ischemic Stroke

The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies

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