Aberrant glycosylation is considered to be a hallmark of colorectal cancer(CRC),as demonstrated by various studies.While the N-glycosylation of cell lines and serum has been widely examined,the analysis of cancer-asso...Aberrant glycosylation is considered to be a hallmark of colorectal cancer(CRC),as demonstrated by various studies.While the N-glycosylation of cell lines and serum has been widely examined,the analysis of cancer-associated N-glycans from tissues has been hampered by the heterogeneity of tumors and the complexity of N-glycan structures.To overcome these obstacles,we present a study using laser capture microdissection that makes it possible to largely deconvolute distinct N-glycomic signatures originating from different regions of heterogeneous tissues including cancerous,stromal,and healthy mucosa cells.N-glycan alditols were analyzed by means of porous graphitized carbon liquid chromatographyelectrospray ionization tandem mass spectrometry,enabling the differentiation and structural characterization of isomeric species.In total,116 N-glycans were identified that showed profound differences in expression among cancer,stroma,and normal mucosa.In comparison with healthy mucosa,the cancer cells showed an increase in a2-6 sialylation and monoantennary N-glycans,as well as a decrease in bisected N-glycans.Moreover,specific sialylated and(sialyl-)LewisA/X antigen-carrying N-glycans were exclusively expressed in cancers.In comparison with cancer,the stroma showed lower levels of oligomannosidic and monoantennary N-glycans,LewisA/X epitopes,and sulfation,as well as increased expression of(core-)fucosylation and a2-3 sialylation.Our study reveals the distinct N-glycomic profiles of different cell types in CRC and control tissues,proving the necessity of their separate analysis for the discovery of cancer-associated glycans.展开更多
Ketodeoxynononic acid(Kdn)is a rather uncommon class of sialic acid in mammals.However,associations have been found between elevated concentrations of free or conjugated Kdn in relation to human cancer progression.Hit...Ketodeoxynononic acid(Kdn)is a rather uncommon class of sialic acid in mammals.However,associations have been found between elevated concentrations of free or conjugated Kdn in relation to human cancer progression.Hitherto,there has been a lack of conclusive evidence that Kdn occurs on(specific)human glycoproteins(conjugated Kdn).Here,we report for the first time that Kdn is expressed on prostate-specific antigen(PSA)N-linked glycans derived from human seminal plasma and urine.Interestingly,Kdn was found only in an a2,3-linkage configuration on an antennary galactose,indicating a highly specific biosynthesis.This unusual glycosylation feature was also identified in a urinary PSA cohort in relation to prostate cancer(PCa),although no differences were found between PCa and nonPCa patients.Further research is needed to investigate the occurrence,biosynthesis,biological role,and biomarker potential of both free and conjugated Kdn in humans.展开更多
Background:This study aimed to identify plasma lipoproteins and small metabolites associated with high risk of malnutrition during intensive care unit(ICU)stay in patients with severe injuries.Methods:This observation...Background:This study aimed to identify plasma lipoproteins and small metabolites associated with high risk of malnutrition during intensive care unit(ICU)stay in patients with severe injuries.Methods:This observational prospective exploratory study was conducted at two level-1 trauma centers in the Netherlands.Adult patients(aged≥18 years)who were admitted to the ICU for more than 48 h between July 2018 and April 2022 owing to severe injuries(polytrauma,as defined by Injury Severity Scores of≥16)caused by blunt trauma were eligible for inclusion.Partial least squares discriminant analysis was used to analyze the relationship of 112 lipoprotein-related components and 23 small metabolites with the risk of malnutrition(mod-ified Nutrition Risk in Critically Ill score).Malnutrition was diagnosed based on Subjective Global Assessment scores.The relationship of lipoprotein properties and small metabolite concentrations with malnutrition(during ICU admission)was evaluated using mixed effects logistic regression.Results:Overall,51 patients were included.Lower(very)low-density lipoprotein([V]LDL)(free)cholesterol and phospholipid levels,low particle number,and higher levels of LDL triglycerides were associated with a higher risk of malnutrition(variable importance in projection[VIP]value>1.5).Low levels of most(V)LDL and intermediate-density lipoprotein subfractions and high levels of high-density lipoprotein Apo-A1 were associated with the diagnosis of malnutrition(VIP value>1.5).Increased levels of dimethyl sulfone,trimethylamine N-oxide,creatinine,N,N-dimethylglycine,and pyruvic acid and decreased levels of creatine,methionine,and acetoacetic acid were also indicative of malnutrition(VIP value>1.5).Overall,14 lipoproteins and 1 small metabolite were significantly associated with a high risk of malnutrition during ICU admission(P<0.05);however,the association did not persist after correcting the false discovery rate(P=0.35 for all).Conclusion:Increased triglyceride in several lipoprotein subfractions and decreased levels of other lipoprotein subfraction lipids and several small metabolites(involved in the homocysteine cycle,ketone body formation,and muscle metabolism)may be indicative of malnutrition risk.Following validation in larger cohorts,these indicators may guide institution of preventive nutritional measures in patients admitted to the ICU with severe injuries.展开更多
Metabolomics is emerging as a powerful tool for studying metabolic processes, identifying crucial biomarkers responsible for metabolic characteristics and revealing metabolic mechanisms, which construct the content of...Metabolomics is emerging as a powerful tool for studying metabolic processes, identifying crucial biomarkers responsible for metabolic characteristics and revealing metabolic mechanisms, which construct the content of discovery metabolomics. The crucial biomarkers can be used to reprogram a metabolome, leading to an aimed metabolic strategy to cope with alteration of internal and external environments, naming reprogramming metabo- Iomics here. The striking feature on the similarity of the basic metabolic pathways and components among vastly different species makes the reprogramming metabolomics possible when the engineered metabolites play biological roles in cellular activity as a substrate of enzymes and a regulator to other molecules including proteins. The reprogramming metabolomics approach can be used to clarify metabolic mechanisms of responding to changed internal and external environmental factors and to estab- lish a framework to develop targeted tools for dealing with the changes such as controlling and/or preventing infec- tion with pathogens and enhancing host immunity against pathogens. This review introduces the current state and trends of discovery metabolomics and reprogramming metabolomics and highlights the importance of repro- gramming metabolomics.展开更多
Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions.Aberrant glycosylation can lead to uncontrolled cell pr...Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions.Aberrant glycosylation can lead to uncontrolled cell proliferation,cell-matrix interactions,migration and differentiation,and has been shown to be involved in cancer and other diseases.The epithelial-to-mesenchymal transition is a key step in the metastatic process by which cancer cells gain the ability to invade tissues and extravasate into the bloodstream.This cellular transformation process,which is associated by morphological change,loss of epithelial traits and gain of mesenchymal markers,is triggered by the secreted cytokine transforming growth factor-β(TGF-β).TGF-βbioactivity is carefully regulated,and its effects on cells are mediated by its receptors on the cell surface.In this review,we first provide a brief overview of major types of glycans,namely,N-glycans,O-glycans,glycosphingolipids and glycosaminoglycans that are involved in cancer progression.Thereafter,we summarize studies on how the glycosylation of TGF-βsignaling components regulates TGF-βsecretion,bioavailability and TGF-βreceptor function.Then,we review glycosylation changes associated with TGF-β-induced epithelial-to-mesenchymal transition in cancer.Identifying and understanding the mechanisms by which glycosylation affects TGF-βsignaling and downstream biological responses will facilitate the identification of glycans as biomarkers and enable novel therapeutic approaches.展开更多
The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis(MS).Emerging evidence indicates that endogenous and dietary-induced changes in fa...The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis(MS).Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity.To date,however,the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood.Here,we report that stearoyl-CoA desaturase-1(SCD1),an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors,acts as an endogenous brake on regulatory T-cell(Treg)differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner.Guided by RNA sequencing and lipidomics analysis,we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase(ATGL).ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma.Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity,with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.展开更多
Dear Editor, Fungal infection involves the invasion of tissues by one or more species of fungi, and this is a serious problem in both medical settings and agriculture [Brown et al., 2012]. Thus, the development of eff...Dear Editor, Fungal infection involves the invasion of tissues by one or more species of fungi, and this is a serious problem in both medical settings and agriculture [Brown et al., 2012]. Thus, the development of efficient strategies for management of these infections is urgently needed [Rodriguez-Martfn et al., 2010]. Recently, a number of antifungal proteins have been reported, including AFP from Aspergillus giganteus, PAF from Penicillium chrysogenum, NAF from Penicillium nalviogense, and AnAFP from Aspergillus niger [Marx et al., 2008; Geisen 2000]. These proteins have demonstrated antifungal activity against opportunistic plant and animal pathogens, such as Fusanum sp., Botrytis sp., and Asper- gillus sp. [Meyer, 2008]. We have previously characterized an antifungal protein （PcPAF） from the culture supernatant of the fungal strain Penicillium citrinum W1, which was isolated from sediment obtained from the Southwest Indian Ocean. PcPAF is thermostable and displays antifungal activity against various pathogenic fungi, including Trichoderma viride, Fusarium oxysporum, Alternaria Iongipes, and Pae- cilomyces variotii [Wen et al., 2014]. Therefore, large-scale production of PcPAF would enable the further drug development of this compound.展开更多
Muscle formation is a coordinated process driven by extensive gene expression changes where single cells fuse together to form multinucleated muscle fibers. Newly synthesized m RNAs are then regulated by RNA binding p...Muscle formation is a coordinated process driven by extensive gene expression changes where single cells fuse together to form multinucleated muscle fibers. Newly synthesized m RNAs are then regulated by RNA binding proteins(RBPs), affecting post-transcriptional transcript metabolism. Here, we determined how large-scale gene expression changes affect the catalog of RBPs by studying proliferating and differentiated muscle cells in healthy and dystrophic conditions. Transcriptomic analysis showed that the expression of more than 7000 genes was affected during myogenesis. We identified 769 RBPs, of which 294 were muscle-specific and 49 were uniquely shared with cardiomyocytes. A subset of 32 RBPs(half of which were muscle-specific) was found to be preferentially associated with target mRNAs in either myoblasts(MBs) or myotubes(MTs). A large proportion of catalytic proteins were bound to mRNAs even though they lack classical RNA binding domains. Finally, we showed how the identification of cell-specific RBPs enabled the identification of biomarkers that can separate healthy individuals from dystrophic patients. Our data show how interactome data can shed light on new basic RNA biology as well as provide cell-specific data that can be used for diagnostic purposes.展开更多
CYP3A5 is a cytochrome P450(CYP)enzyme that metabolizes drugs and contributes to drug resistance in cancer.However,it remains unclear whether CYP3A5 directly influences cancer progression.In this report,we demonstrate...CYP3A5 is a cytochrome P450(CYP)enzyme that metabolizes drugs and contributes to drug resistance in cancer.However,it remains unclear whether CYP3A5 directly influences cancer progression.In this report,we demonstrate that CYP3A5 regulates glucose metabolism in pancreatic ductal adenocarcinoma.Multi-omics analysis showed that CYP3A5 knockdown re-sults in a decrease in various glucose-related metabolites through its effect on glucose trans-port.A mechanistic study revealed that CYP3A5 enriches the glucose transporter GLUT1 at the plasma membrane by restricting the translation of TXNIP,a negative regulator of GLUT1.Notably,CYP3A5-generated reactive oxygen species were proved to be responsible for atten-uating the AKT-4EBP1-TXNIP signaling pathway.CYP3A5 contributes to cell migration by maintaining high glucose uptake in pancreatic cancer.Taken together,our results,for the first time,reveal a role of CYP3A5 in glucose metabolism in pancreatic ductal adenocarcinoma and identify a novel mechanism that is a potential therapeutic target.展开更多
文摘Aberrant glycosylation is considered to be a hallmark of colorectal cancer(CRC),as demonstrated by various studies.While the N-glycosylation of cell lines and serum has been widely examined,the analysis of cancer-associated N-glycans from tissues has been hampered by the heterogeneity of tumors and the complexity of N-glycan structures.To overcome these obstacles,we present a study using laser capture microdissection that makes it possible to largely deconvolute distinct N-glycomic signatures originating from different regions of heterogeneous tissues including cancerous,stromal,and healthy mucosa cells.N-glycan alditols were analyzed by means of porous graphitized carbon liquid chromatographyelectrospray ionization tandem mass spectrometry,enabling the differentiation and structural characterization of isomeric species.In total,116 N-glycans were identified that showed profound differences in expression among cancer,stroma,and normal mucosa.In comparison with healthy mucosa,the cancer cells showed an increase in a2-6 sialylation and monoantennary N-glycans,as well as a decrease in bisected N-glycans.Moreover,specific sialylated and(sialyl-)LewisA/X antigen-carrying N-glycans were exclusively expressed in cancers.In comparison with cancer,the stroma showed lower levels of oligomannosidic and monoantennary N-glycans,LewisA/X epitopes,and sulfation,as well as increased expression of(core-)fucosylation and a2-3 sialylation.Our study reveals the distinct N-glycomic profiles of different cell types in CRC and control tissues,proving the necessity of their separate analysis for the discovery of cancer-associated glycans.
基金supported by the Chinese Scholarship CouncilCure for Cancer FoundationAstellas Pharma B.V。
文摘Ketodeoxynononic acid(Kdn)is a rather uncommon class of sialic acid in mammals.However,associations have been found between elevated concentrations of free or conjugated Kdn in relation to human cancer progression.Hitherto,there has been a lack of conclusive evidence that Kdn occurs on(specific)human glycoproteins(conjugated Kdn).Here,we report for the first time that Kdn is expressed on prostate-specific antigen(PSA)N-linked glycans derived from human seminal plasma and urine.Interestingly,Kdn was found only in an a2,3-linkage configuration on an antennary galactose,indicating a highly specific biosynthesis.This unusual glycosylation feature was also identified in a urinary PSA cohort in relation to prostate cancer(PCa),although no differences were found between PCa and nonPCa patients.Further research is needed to investigate the occurrence,biosynthesis,biological role,and biomarker potential of both free and conjugated Kdn in humans.
文摘Background:This study aimed to identify plasma lipoproteins and small metabolites associated with high risk of malnutrition during intensive care unit(ICU)stay in patients with severe injuries.Methods:This observational prospective exploratory study was conducted at two level-1 trauma centers in the Netherlands.Adult patients(aged≥18 years)who were admitted to the ICU for more than 48 h between July 2018 and April 2022 owing to severe injuries(polytrauma,as defined by Injury Severity Scores of≥16)caused by blunt trauma were eligible for inclusion.Partial least squares discriminant analysis was used to analyze the relationship of 112 lipoprotein-related components and 23 small metabolites with the risk of malnutrition(mod-ified Nutrition Risk in Critically Ill score).Malnutrition was diagnosed based on Subjective Global Assessment scores.The relationship of lipoprotein properties and small metabolite concentrations with malnutrition(during ICU admission)was evaluated using mixed effects logistic regression.Results:Overall,51 patients were included.Lower(very)low-density lipoprotein([V]LDL)(free)cholesterol and phospholipid levels,low particle number,and higher levels of LDL triglycerides were associated with a higher risk of malnutrition(variable importance in projection[VIP]value>1.5).Low levels of most(V)LDL and intermediate-density lipoprotein subfractions and high levels of high-density lipoprotein Apo-A1 were associated with the diagnosis of malnutrition(VIP value>1.5).Increased levels of dimethyl sulfone,trimethylamine N-oxide,creatinine,N,N-dimethylglycine,and pyruvic acid and decreased levels of creatine,methionine,and acetoacetic acid were also indicative of malnutrition(VIP value>1.5).Overall,14 lipoproteins and 1 small metabolite were significantly associated with a high risk of malnutrition during ICU admission(P<0.05);however,the association did not persist after correcting the false discovery rate(P=0.35 for all).Conclusion:Increased triglyceride in several lipoprotein subfractions and decreased levels of other lipoprotein subfraction lipids and several small metabolites(involved in the homocysteine cycle,ketone body formation,and muscle metabolism)may be indicative of malnutrition risk.Following validation in larger cohorts,these indicators may guide institution of preventive nutritional measures in patients admitted to the ICU with severe injuries.
文摘Metabolomics is emerging as a powerful tool for studying metabolic processes, identifying crucial biomarkers responsible for metabolic characteristics and revealing metabolic mechanisms, which construct the content of discovery metabolomics. The crucial biomarkers can be used to reprogram a metabolome, leading to an aimed metabolic strategy to cope with alteration of internal and external environments, naming reprogramming metabo- Iomics here. The striking feature on the similarity of the basic metabolic pathways and components among vastly different species makes the reprogramming metabolomics possible when the engineered metabolites play biological roles in cellular activity as a substrate of enzymes and a regulator to other molecules including proteins. The reprogramming metabolomics approach can be used to clarify metabolic mechanisms of responding to changed internal and external environmental factors and to estab- lish a framework to develop targeted tools for dealing with the changes such as controlling and/or preventing infec- tion with pathogens and enhancing host immunity against pathogens. This review introduces the current state and trends of discovery metabolomics and reprogramming metabolomics and highlights the importance of repro- gramming metabolomics.
文摘Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions.Aberrant glycosylation can lead to uncontrolled cell proliferation,cell-matrix interactions,migration and differentiation,and has been shown to be involved in cancer and other diseases.The epithelial-to-mesenchymal transition is a key step in the metastatic process by which cancer cells gain the ability to invade tissues and extravasate into the bloodstream.This cellular transformation process,which is associated by morphological change,loss of epithelial traits and gain of mesenchymal markers,is triggered by the secreted cytokine transforming growth factor-β(TGF-β).TGF-βbioactivity is carefully regulated,and its effects on cells are mediated by its receptors on the cell surface.In this review,we first provide a brief overview of major types of glycans,namely,N-glycans,O-glycans,glycosphingolipids and glycosaminoglycans that are involved in cancer progression.Thereafter,we summarize studies on how the glycosylation of TGF-βsignaling components regulates TGF-βsecretion,bioavailability and TGF-βreceptor function.Then,we review glycosylation changes associated with TGF-β-induced epithelial-to-mesenchymal transition in cancer.Identifying and understanding the mechanisms by which glycosylation affects TGF-βsignaling and downstream biological responses will facilitate the identification of glycans as biomarkers and enable novel therapeutic approaches.
基金supported by the Flemish Fund for Scientific Research(FWO Vlaanderen,12J9116N,12JG119N,12U7718N,1S15519N,and G099618N)the Belgian Charcot Foundation(FCS-2016-EG7,R-8676,and R-6832)+4 种基金the Interreg V‐A EMR program(EURLIPIDS,EMR23)the special research fund UHasselt(BOF)JMN is supported by a National Institutes of Health Grant(R01 DK062388)supported by the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation program(640116)by a SALK grant from the government of Flanders and by an Odysseus grant of the Research Foundation Flanders,Belgium(FWO).
文摘The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis(MS).Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity.To date,however,the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood.Here,we report that stearoyl-CoA desaturase-1(SCD1),an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors,acts as an endogenous brake on regulatory T-cell(Treg)differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner.Guided by RNA sequencing and lipidomics analysis,we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase(ATGL).ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma.Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity,with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.
基金the Comra fund Grant （DY125-15-T-07）, the National Natural Science Foundation of China （Grant Nos. 30972279 and 40976080）, and the National Basic Research Program （973 Program） （No. 2015CB755903）.
文摘Dear Editor, Fungal infection involves the invasion of tissues by one or more species of fungi, and this is a serious problem in both medical settings and agriculture [Brown et al., 2012]. Thus, the development of efficient strategies for management of these infections is urgently needed [Rodriguez-Martfn et al., 2010]. Recently, a number of antifungal proteins have been reported, including AFP from Aspergillus giganteus, PAF from Penicillium chrysogenum, NAF from Penicillium nalviogense, and AnAFP from Aspergillus niger [Marx et al., 2008; Geisen 2000]. These proteins have demonstrated antifungal activity against opportunistic plant and animal pathogens, such as Fusanum sp., Botrytis sp., and Asper- gillus sp. [Meyer, 2008]. We have previously characterized an antifungal protein （PcPAF） from the culture supernatant of the fungal strain Penicillium citrinum W1, which was isolated from sediment obtained from the Southwest Indian Ocean. PcPAF is thermostable and displays antifungal activity against various pathogenic fungi, including Trichoderma viride, Fusarium oxysporum, Alternaria Iongipes, and Pae- cilomyces variotii [Wen et al., 2014]. Therefore, large-scale production of PcPAF would enable the further drug development of this compound.
基金Prinses Beatrix Spierfonds in the Netherlands(Grant No.W.OR.14-13)
文摘Muscle formation is a coordinated process driven by extensive gene expression changes where single cells fuse together to form multinucleated muscle fibers. Newly synthesized m RNAs are then regulated by RNA binding proteins(RBPs), affecting post-transcriptional transcript metabolism. Here, we determined how large-scale gene expression changes affect the catalog of RBPs by studying proliferating and differentiated muscle cells in healthy and dystrophic conditions. Transcriptomic analysis showed that the expression of more than 7000 genes was affected during myogenesis. We identified 769 RBPs, of which 294 were muscle-specific and 49 were uniquely shared with cardiomyocytes. A subset of 32 RBPs(half of which were muscle-specific) was found to be preferentially associated with target mRNAs in either myoblasts(MBs) or myotubes(MTs). A large proportion of catalytic proteins were bound to mRNAs even though they lack classical RNA binding domains. Finally, we showed how the identification of cell-specific RBPs enabled the identification of biomarkers that can separate healthy individuals from dystrophic patients. Our data show how interactome data can shed light on new basic RNA biology as well as provide cell-specific data that can be used for diagnostic purposes.
基金supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM118041.
文摘CYP3A5 is a cytochrome P450(CYP)enzyme that metabolizes drugs and contributes to drug resistance in cancer.However,it remains unclear whether CYP3A5 directly influences cancer progression.In this report,we demonstrate that CYP3A5 regulates glucose metabolism in pancreatic ductal adenocarcinoma.Multi-omics analysis showed that CYP3A5 knockdown re-sults in a decrease in various glucose-related metabolites through its effect on glucose trans-port.A mechanistic study revealed that CYP3A5 enriches the glucose transporter GLUT1 at the plasma membrane by restricting the translation of TXNIP,a negative regulator of GLUT1.Notably,CYP3A5-generated reactive oxygen species were proved to be responsible for atten-uating the AKT-4EBP1-TXNIP signaling pathway.CYP3A5 contributes to cell migration by maintaining high glucose uptake in pancreatic cancer.Taken together,our results,for the first time,reveal a role of CYP3A5 in glucose metabolism in pancreatic ductal adenocarcinoma and identify a novel mechanism that is a potential therapeutic target.
