The cytochrome P450 enzyme CYP4F11,a pivotal regulator of fatty acid metabolism and drug metabolism,exhibits significantly overexpression in non-small cell lung cancer(NSCLC)and is associated with poor clinical outcom...The cytochrome P450 enzyme CYP4F11,a pivotal regulator of fatty acid metabolism and drug metabolism,exhibits significantly overexpression in non-small cell lung cancer(NSCLC)and is associated with poor clinical outcomes.Through integrated analysis of TCGA/GEO datasets and immunohistochemistry validation of 235 NSCLC specimens,we established CYP4F11 as a novel prognostic biomarker.Functional studies demonstrated that CYP4F11 knockdown markedly impaired NSCLC cell proliferation,clonogenicity,and migration in vitro,moreover xenograft models confirmed its tumor-promoting role in vivo.Mechanistically,we identified CYP4F11 as a direct target of tumor suppressor miR-195 via 3′-UTR binding,with miR-195-mediated suppression of CYP4F11 leading to ubiquitin-proteasomal degradation of mitochondrial malic enzyme 2(ME2)—a critical metabolic regulator in cancer cells.Metabolomic analyses revealed that CYP4F11 depletion disrupts mitochondrial malate metabolism,while rescue experiments confirmed ME2’s pivotal role in mediating CYP4F11’s oncogenic effects.Our findings elucidate the CYP4F11/miR-195/ME2 regulatory axis as a crucial determinant of NSCLC progression,highlighting CYP4F11 as both a prognostic indicator and a potential therapeutic target through modulation of cancer cell metabolism.展开更多
Monoacylglycerol lipase(MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol(2-AG) into the proinflammatory eicosanoid precursor arachidonic acid(AA). MAGL and other endoge...Monoacylglycerol lipase(MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol(2-AG) into the proinflammatory eicosanoid precursor arachidonic acid(AA). MAGL and other endogenous cannabinoid(EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell(HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an;F-labeled MAGL inhibitor([18F]MAGL-4-11)for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [18F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation(BDL) and carbon tetrachloride(CCl_(4)) models of liver cirrhosis;we also assessed the hepatic gene expression of the enzymes involved with EC system including MAGL, NAPE-PLD, FAAH and DAGL that as a function of disease severity in these models;[18F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human. [18F]MAGL-4-11 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice. We confirmed MAGL and FAAH expression decreases with fibrosisseverity, while its levels in normal liver tissue are high;in contrast, the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models. In vitro autoradiography further supported that[18F]MAGL-4-11 bound specifically to MAGL in both animal and human fibrotic liver tissues. Our PET ligand [18F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82060529 and 82172748)the Guangdong Basic and Applied Basic Research Foundation(No.2023A1515110567).
文摘The cytochrome P450 enzyme CYP4F11,a pivotal regulator of fatty acid metabolism and drug metabolism,exhibits significantly overexpression in non-small cell lung cancer(NSCLC)and is associated with poor clinical outcomes.Through integrated analysis of TCGA/GEO datasets and immunohistochemistry validation of 235 NSCLC specimens,we established CYP4F11 as a novel prognostic biomarker.Functional studies demonstrated that CYP4F11 knockdown markedly impaired NSCLC cell proliferation,clonogenicity,and migration in vitro,moreover xenograft models confirmed its tumor-promoting role in vivo.Mechanistically,we identified CYP4F11 as a direct target of tumor suppressor miR-195 via 3′-UTR binding,with miR-195-mediated suppression of CYP4F11 leading to ubiquitin-proteasomal degradation of mitochondrial malic enzyme 2(ME2)—a critical metabolic regulator in cancer cells.Metabolomic analyses revealed that CYP4F11 depletion disrupts mitochondrial malate metabolism,while rescue experiments confirmed ME2’s pivotal role in mediating CYP4F11’s oncogenic effects.Our findings elucidate the CYP4F11/miR-195/ME2 regulatory axis as a crucial determinant of NSCLC progression,highlighting CYP4F11 as both a prognostic indicator and a potential therapeutic target through modulation of cancer cell metabolism.
基金supported by MGH Research Scholars Program(to Raymond.T.Chung,USA)。
文摘Monoacylglycerol lipase(MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol(2-AG) into the proinflammatory eicosanoid precursor arachidonic acid(AA). MAGL and other endogenous cannabinoid(EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell(HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an;F-labeled MAGL inhibitor([18F]MAGL-4-11)for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [18F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation(BDL) and carbon tetrachloride(CCl_(4)) models of liver cirrhosis;we also assessed the hepatic gene expression of the enzymes involved with EC system including MAGL, NAPE-PLD, FAAH and DAGL that as a function of disease severity in these models;[18F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human. [18F]MAGL-4-11 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice. We confirmed MAGL and FAAH expression decreases with fibrosisseverity, while its levels in normal liver tissue are high;in contrast, the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models. In vitro autoradiography further supported that[18F]MAGL-4-11 bound specifically to MAGL in both animal and human fibrotic liver tissues. Our PET ligand [18F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues.
