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1.
J Clin Invest ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34609966

RESUMO

Ferroptosis, an iron-dependent non-apoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here we reported that the RNA binding protein RBMS1 participated in lung cancer development through mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 was a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3'- and 5'-UTRs of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake and promotes ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potentials and clinical values.

2.
Se Pu ; 39(10): 1118-1127, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34505434

RESUMO

The late endosomal/lysosomal adaptor MAPK and mTOR activator 1 (LAMTOR1) is an important regulator protein in the response to energy stress. Public gene expression data shows that the expression of LAMTOR1 is abnormally high in nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC); hence, LAMTOR1 may play an important role in the development of NASH and HCC. Therefore, exploring the LAMTOR1 regulatory mechanism in the progression of NASH and malignant transformation of liver inflammation may be crucial for translational medicine. First, a NASH mouse model was established by feeding a methionine choline-deficient (MCD) diet. Hematoxylin-eosin staining of liver tissues showed successful modeling of inflammatory injury in the mouse liver. Immunoblot analysis confirmed LAMTOR1- and LAMTOR1-mediated protein expression in LAMTOR1 specifically depleted mouse livers. Subsequently, metabolic profiling of liver tissues was performed using an ultra-performance liquid chromatography-time-of-flight mass spectrometry strategy. Based on the retention time, m/z value, and tandem mass spectra, 134 metabolites were identified. Among these, the levels of 45 metabolite were significantly influenced by hepatic LAMTOR1 depletion. According to the metabolomics results, uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) was significantly upregulated in LAMTOR1-depleted (LAMTOR1LKO) hepatocyte tissues. As the final product of the hexosamine biosynthetic pathway (HBP), alteration in UDP-GlcNAc levels may regulate LAMTOR1 and metabolic regulatory genes downstream of HBP. Moreover, there was an obvious increase in the levels of several methylation-related metabolites. Thus, upregulated S-adenosylmethionine, S-adenosylhomocysteine, and N6,N6,N6-trimethyl-L-lysine indicated that LAMTOR1 may regulate the process of DNA or protein methylation. In addition, downregulation of 9-oxo-octadecadienoate, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) was also observed in LAMTOR1LKO mice liver tissues. Alterations in polyunsaturated fatty acids, such as EPA and DHA, link LAMTOR1 to inflammatory and immune processes, which are known to play important roles in NASH pathogenesis. These metabolic disorders demonstrated that LAMTOR1 significantly contributed to the metabolic mechanism of NASH. Furthermore, gene expression correlations were analyzed to interpret the regulatory role of LAMTOR1 from the perspective of genetic networks. Owing to a paucity of liver whole-transcriptome studies in NASH, correlation analysis was performed based on HCC transcriptome data from public databases. First, a negatively regulated relationship was observed between LAMTOR1 and MAT1A (R=-0.47). MAT1A encodes methionine adenosyltransferase 1A, an essential enzyme that catalyzes the formation of S-adenosylmethionine. Based on the upregulation of UDP-GlcNAc under hepatocyte LAMTOR1 depletion, it was predicted that LAMTOR1 positively influenced MGAT1 (R=0.47), a gene encoding alpha-1,3-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase. Together with changes in succinyladenosine caused by hepatocyte LAMTOR1 deletion, predicted correlation results showed that LAMTOR1 may also participate in the pathogenesis through the positive regulatory relationship with ADSL (R=0.59). The ADSL gene provides instructions for making an enzyme called adenylosuccinate lyase, which can dephosphorylate the substrate succinyladenosine. In this study, LAMTOR1 was identified to specifically regulate multiple key metabolic pathways based on both NASH mouse models and gene expression correlations. These results illustrate the important role of LAMTOR1 in the progression of NASH and malignant transformation of liver inflammation, which provides a theoretical basis for the diagnosis and treatment of NASH or possible NASH-driven HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Cromatografia Líquida , Modelos Animais de Doenças , Inflamação , Fígado , Espectrometria de Massas , Metionina , Camundongos
3.
Artigo em Inglês | MEDLINE | ID: mdl-34519394

RESUMO

Although super-resolution imaging offers an opportunity to visualize cellular structures and organelles at the nanoscale level, cellular heterogeneity and unpredictability still pose a significant challenge in the dynamic imaging of live cells. It is thus vital to develop better performing and more photostable probes for long-term super-resolution imaging. Herein, we report a probe LD-FG for imaging lipid droplet (LD) dynamics using structured illumination microscopy (SIM). LD-FG allows wash-free imaging of LDs, owing to hydrogen-bond sensitive fluorogenicity. The replenishment of photobleached LD-FG by intact ones outside LDs further ensure the long-time stability of the fluorescence imaging. With this buffering fluorogenic probe, fast and unpredictable dynamic processes of LDs can be visualized. Two LD coalescence modes (as well as heterogeneity in different regions of the cells and even in between different cells) were discovered for the first time. Notably, the dynamic imaging also allowed us to propose a new model of LD maturation during adipocyte differentiation, i.e. , a fast LD coalescence followed by a slow ripening step. The excellent performance of LD-FG makes the buffer strategy an effective method for designing fluorescent probes for cell dynamic imaging.

4.
Adv Sci (Weinh) ; 8(17): e2100311, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34247449

RESUMO

Metabolite-protein interactions (MPIs) play key roles in cancer metabolism. However, our current knowledge about MPIs in cancers remains limited due to the complexity of cancer cells. Herein, the authors construct an integrative MPI network and propose a MPI network based hepatocellular carcinoma (HCC) subtyping and mechanism exploration workflow. Based on the expressions of hub proteins on the MPI network, two prognosis-distinctive HCC subtypes are identified. Meanwhile, multiple interdependent features of the poor prognostic subtype are observed, including hypoxia, DNA hypermethylation of metabolic pathways, fatty acid accumulation, immune pathway up-regulation, and exhausted T-cell infiltration. Notably, the immune pathway up-regulation is probably induced by accumulated unsaturated fatty acids which are predicted to interact with multiple immune regulators like SRC and TGFB1. Moreover, based on tumor microenvironment compositions, the poor prognostic subtype is further divided into two sub-populations showing remarkable differences in metabolism. The subtyping shows a strong consistency across multiple HCC cohorts including early-stage HCC. Overall, the authors redefine robust HCC prognosis subtypes and identify potential MPIs linking metabolism to immune regulations, thus promoting understanding and clinical applications about HCC metabolism heterogeneity.

5.
Cancer Sci ; 112(8): 3278-3292, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34091997

RESUMO

It is widely accepted that redox reprogramming participates in malignant transformation of lung adenocarcinoma (LUAD). However, the source of excessive reactive oxygen species (ROS) and the downstream signaling regulatory mechanism are complicated and unintelligible. In the current study, we newly identified the aquaporin 3 (AQP3) as a LUAD oncogenic factor with capacity to transport exogenous hydrogen peroxide (H2 O2 ) and increase intracellular ROS levels. Subsequently, we demonstrated that AQP3 was necessary for the facilitated diffusion of exogenous H2 O2 in LUAD cells and that the AQP3-dependent transport of H2 O2 accelerated cell growth and inhibited rapamycin-induced autophagy. Mechanistically, AQP3-mediated H2 O2 uptake increased intracellular ROS levels to inactivate PTEN and activate the AKT/mTOR pathway to subsequently inhibit autophagy and promote proliferation in LUAD cells. Finally, we suggested that AQP3 depletion retarded subcutaneous tumorigenesis in vivo and simultaneously decreased ROS levels and promoted autophagy. These findings underscore the importance of AQP3-induced oxidative stress in malignant transformation and suggest a therapeutic target for LUAD.


Assuntos
Adenocarcinoma de Pulmão/patologia , Aquaporina 3/genética , Aquaporina 3/metabolismo , Peróxido de Hidrogênio/metabolismo , Neoplasias Pulmonares/patologia , PTEN Fosfo-Hidrolase/metabolismo , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Transplante de Neoplasias , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Sirolimo/farmacologia
6.
Cancer Commun (Lond) ; 41(7): 576-595, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34110104

RESUMO

BACKGROUND: Y-box binding protein 1 (YB1 or YBX1) plays a critical role in tumorigenesis and cancer progression. However, whether YB1 affects malignant transformation by modulating non-coding RNAs remains largely unknown. This study aimed to investigate the relationship between YB1 and microRNAs and reveal the underlying mechanism by which YB1 impacts on tumor malignancy via miRNAs-mediated regulatory network. METHODS: The biological functions of YB1 in hepatocellular carcinoma (HCC) cells were investigated by cell proliferation, wound healing, and transwell invasion assays. The miRNAs dysregulated by YB1 were screened by microarray analysis in HCC cell lines. The regulation of YB1 on miR-205 and miR-200b was determined by quantitative real-time PCR, dual-luciferase reporter assay, RNA immunoprecipitation, and pull-down assay. The relationships of YB1, DGCR8, Dicer, TUT4, and TUT1 were identified by pull-down and coimmunoprecipitation experiments. The cellular co-localization of YB1, DGCR8, and Dicer were detected by immunofluorescent staining. The in vivo effect of YB1 on tumor metastasis was determined by injecting MHCC97H cells transduced with YB1 shRNA or shControl via the tail vein in nude BALB/c mice. The expression levels of epithelial to mesenchymal transition markers were detected by immunoblotting and immunohistochemistry assays. RESULTS: YB1 promoted HCC cell migration and tumor metastasis by regulating miR-205/200b-ZEB1 axis partially in a Snail-independent manner. YB1 suppressed miR-205 and miR-200b maturation by interacting with the microprocessors DGCR8 and Dicer as well as TUT4 and TUT1 via the conserved cold shock domain. Subsequently, the downregulation of miR-205 and miR-200b enhanced ZEB1 expression, thus leading to increased cell migration and invasion. Furthermore, statistical analyses on gene expression data from HCC and normal liver tissues showed that YB1 expression was positively associated with ZEB1 expression and remarkably correlated with clinical prognosis. CONCLUSION: This study reveals a previously undescribed mechanism by which YB1 promotes cancer progression by regulating the miR-205/200b-ZEB1 axis in HCC cells. Furthermore, these results highlight that YB1 may play biological functions via miRNAs-mediated gene regulation, and it can serve as a potential therapeutic target in human cancers.

7.
Angew Chem Int Ed Engl ; 60(29): 16067-16076, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-33991044

RESUMO

Unlike amyloid aggregates, amorphous protein aggregates with no defined structures have been challenging to target and detect in a complex cellular milieu. In this study, we rationally designed sensors of amorphous protein aggregation from aggregation-induced-emission probes (AIEgens). Utilizing dicyanoisophorone as a model AIEgen scaffold, we first sensitized the fluorescence of AIEgens to a nonpolar and viscous environment mimicking the interior of amorphous aggregated proteins. We identified a generally applicable moiety (dimethylaminophenylene) for selective binding and fluorescence enhancement. Regulation of the electron-withdrawing groups tuned the emission wavelength while retaining selective detection. Finally, we utilized the optimized probe to systematically image aggregated proteome upon proteostasis network regulation. Overall, we present a rational approach to develop amorphous protein aggregation sensors from AIEgens with controllable sensitivity, spectral coverage, and cellular performance.


Assuntos
Desenho de Fármacos , Agregados Proteicos , Amiloide/química , Sobrevivência Celular , Cristalização , Corantes Fluorescentes/química
8.
Cell Metab ; 33(6): 1111-1123.e4, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33811821

RESUMO

As one of the most popular nutrient supplements, creatine has been highly used to increase muscle mass and improve exercise performance. Here, we report an adverse effect of creatine using orthotopic mouse models, showing that creatine promotes colorectal and breast cancer metastasis and shortens mouse survival. We show that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, is upregulated in liver metastases. Dietary uptake, or GATM-mediated de novo synthesis of creatine, enhances cancer metastasis and shortens mouse survival by upregulation of Snail and Slug expression via monopolar spindle 1 (MPS1)-activated Smad2 and Smad3 phosphorylation. GATM knockdown or MPS1 inhibition suppresses cancer metastasis and benefits mouse survival by downregulating Snail and Slug. Our findings call for using caution when considering dietary creatine to improve muscle mass or treat diseases and suggest that targeting GATM or MPS1 prevents cancer metastasis, especially metastasis of transforming growth factor beta receptor mutant colorectal cancers.

9.
Theranostics ; 11(10): 4839-4857, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754031

RESUMO

Reactive oxygen species (ROS) serve as cell signaling molecules generated in oxidative metabolism and are associated with a number of human diseases. The reprogramming of redox metabolism induces abnormal accumulation of ROS in cancer cells. It has been widely accepted that ROS play opposite roles in tumor growth, metastasis and apoptosis according to their different distributions, concentrations and durations in specific subcellular structures. These double-edged roles in cancer progression include the ROS-dependent malignant transformation and the oxidative stress-induced cell death. In this review, we summarize the notable literatures on ROS generation and scavenging, and discuss the related signal transduction networks and corresponding anticancer therapies. There is no doubt that an improved understanding of the sophisticated mechanism of redox biology is imperative to conquer cancer.


Assuntos
Carcinogênese , Proliferação de Células , Transição Epitelial-Mesenquimal , Neoplasias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Morte Celular Regulada , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Apoptose , Ferroptose , Humanos , Mitocôndrias/metabolismo , NADP/metabolismo , NADPH Oxidases/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Necroptose , Neoplasias/prevenção & controle , Neoplasias/terapia , Oxirredução , Estresse Oxidativo , Transdução de Sinais , Superóxido Dismutase/metabolismo
10.
Nat Metab ; 3(1): 90-106, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398195

RESUMO

Organelles use specialized molecules to regulate their essential cellular processes. However, systematically elucidating the subcellular distribution and function of molecules such as long non-coding RNAs (lncRNAs) in cellular homeostasis and diseases has not been fully achieved. Here, we reveal the diverse and abundant subcellular distribution of organelle-associated lncRNAs from mitochondria, lysosomes and endoplasmic reticulum. Among them, we identify the mitochondrially localized lncRNA growth-arrest-specific 5 (GAS5) as a tumour suppressor in maintaining cellular energy homeostasis. Mechanistically, energy-stress-induced GAS5 modulates mitochondrial tricarboxylic acid flux by disrupting metabolic enzyme tandem association of fumarate hydratase, malate dehydrogenase and citrate synthase, the canonical members of the tricarboxylic acid cycle. GAS5 negatively correlates with levels of its associated mitochondrial metabolic enzymes in tumours and benefits overall survival in individuals with breast cancer. Together, our detailed annotation of subcellular lncRNA distribution identifies a functional role for lncRNAs in regulating cellular metabolic homeostasis, highlighting organelle-associated lncRNAs as potential clinical targets to manipulate cellular metabolism and diseases.


Assuntos
Ciclo do Ácido Cítrico/fisiologia , Mitocôndrias/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Feminino , Homeostase , Humanos , Lisossomos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Nutrientes , Organelas/metabolismo , RNA Neoplásico/genética
11.
Mol Oncol ; 15(2): 642-656, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33207079

RESUMO

Dependence on glutamine and acceleration of fatty acid oxidation (FAO) are both metabolic characteristics of triple-negative breast cancer (TNBC). With the rapid growth of tumors, accelerated glutamine catabolism depletes local glutamine, resulting in glutamine deficiency. Studies have shown that the use of alternative energy sources, such as fatty acids, enables tumor cells to continue to proliferate rapidly in a glutamine-deficient microenvironment. However, the detailed mechanisms behind this metabolic change are still unclear. Herein, we identified HRD1 as a regulatory protein for FAO that specifically inhibits TNBC cell proliferation under glutamine-deficient conditions. Furthermore, we observed that HRD1 expression is significantly downregulated under glutamine deprivation and HRD1 directly ubiquitinates and stabilizes CPT2 through K48-linked ubiquitination. In addition, the inhibition of CPT2 expression dramatically suppresses TNBC cell proliferation mediated by HRD1 knockdown in vitro and in vivo. Finally, we found that the glutaminase inhibitor CB839 significantly inhibited TNBC cell tumor growth, but not in the HRD1 knock-downed TNBC cells. These findings provide an invaluable insight into HRD1 as a regulator of lipid metabolism and have important implications for TNBC therapeutic targeting.

13.
BMC Med Genomics ; 13(1): 118, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32831081

RESUMO

BACKGROUND: DNA methylation is a common chemical modification of DNA in the carcinogenesis of hepatocellular carcinoma (HCC). METHODS: In this bioinformatics analysis, 348 liver cancer samples were collected from the Cancer Genome Atlas (TCGA) database to analyse specific DNA methylation sites that affect the prognosis of HCC patients. RESULTS: 10,699 CpG sites (CpGs) that were significantly related to the prognosis of patients were clustered into 7 subgroups, and the samples of each subgroup were significantly different in various clinical pathological data. In addition, by calculating the level of methylation sites in each subgroup, 119 methylation sites (corresponding to 105 genes) were selected as specific methylation sites within the subgroups. Moreover, genes in the corresponding promoter regions in which the above specific methylation sites were located were subjected to signalling pathway enrichment analysis, and it was discovered that these genes were enriched in the biological pathways that were reported to be closely correlated with HCC. Additionally, the transcription factor enrichment analysis revealed that these genes were mainly enriched in the transcription factor KROX. A naive Bayesian classification model was used to construct a prognostic model for HCC, and the training and test data sets were used for independent verification and testing. CONCLUSION: This classification method can well reflect the heterogeneity of HCC samples and help to develop personalized treatment and accurately predict the prognosis of patients.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Ilhas de CpG , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Regiões Promotoras Genéticas , Teorema de Bayes , Carcinoma Hepatocelular/classificação , Carcinoma Hepatocelular/genética , Epigênese Genética , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/genética
14.
Research (Wash D C) ; 2020: 7043124, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32377639

RESUMO

Glutathione S-transferases (GSTs), detoxification enzymes that catalyze the addition of glutathione (GSH) to diverse electrophilic molecules, are often overexpressed in various tumor cells. While fluorescent probes for GSTs have often adopted the 2,4-dinitrobenzenesulfonyl (DNs) group as the receptor unit, they usually suffer from considerable background reaction noise with GSH due to excessive electron deficiency. However, weakening this reactivity is generally accompanied by loss of sensitivity for GSTs, and therefore, finely turning down the reactivity while maintaining certain sensitivity is critical for developing a practical probe. Here, we report a rational semiquantitative strategy for designing such a practical two-photon probe by introducing a parameter adopted from the conceptual density functional theory (CDFT), the local electrophilicity ω k , to characterize this reactivity. As expected, kinetic studies established ω k as efficient to predict the reactivity with GSH, and probe NI3 showing the best performance was successfully applied to detecting GST activities in live cells and tissue sections with high sensitivity and signal-to-noise ratio. Photoinduced electron transfer of naphthalimide-based probes, captured by femtosecond transient absorption for the first time and unraveled by theoretical calculations, also contributes to the negligible background noise.

15.
Theranostics ; 10(9): 4150-4167, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226545

RESUMO

E3 ubiquitin ligases play a critical role in cellular mechanisms and cancer progression. F-box protein is the core component of the SKP1-cullin 1-F-box (SCF)-type E3 ubiquitin ligase and directly binds to substrates by various specific domains. According to the specific domains, F-box proteins are further classified into three sub-families: 1) F-box with leucine rich amino acid repeats (FBXL); 2) F-box with WD 40 amino acid repeats (FBXW); 3) F-box only with uncharacterized domains (FBXO). Here, we summarize the substrates of F-box proteins, discuss the important molecular mechanism and emerging role of F-box proteins especially from the perspective of cancer development and progression. These findings will shed new light on malignant tumor progression mechanisms, and suggest the potential role of F-box proteins as cancer biomarkers and therapeutic targets for future cancer treatment.


Assuntos
Proteínas F-Box , Neoplasias/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas F-Box/antagonistas & inibidores , Proteínas F-Box/metabolismo , Humanos , Ligantes , Camundongos , Transdução de Sinais , Ubiquitinação
16.
Adv Sci (Weinh) ; 7(7): 1902996, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32274306

RESUMO

Acute-on-chronic liver failure (ACLF) has a high mortality rate. Metabolic reprogramming is an important mechanism for cell survival. Herein, the metabolic patterns of ACLF patients are analyzed. An in vitro model of ACLF is established using Chang liver cells under hyperammonemia and hypoxia. A randomized clinical trial (ChiCTR-OPC-15006839) is performed with patients receiving L-ornithine and L-aspartate (LOLA) daily intravenously (LOLA group) and trimetazidine (TMZ) tid orally (TMZ group) based on conventional treatment (control group). The primary end point is 90-day overall survival, and overall survival is the secondary end point. By analyzing metabolic profiles in liver tissue samples from hepatitis B virus (HBV)-related ACLF patients and the controls, the metabolic characteristics of HBV-related ACLF patients are identified: inhibited glycolysis, tricarboxylic acid cycle and urea cycle, and enhanced fatty acid oxidation (FAO) and glutamine anaplerosis. These effects are mainly attributed to hyperammonemia and hypoxia. Further in vitro study reveals that switching from FAO to glycolysis could improve hepatocyte survival in the hyperammonemic and hypoxic microenvironment. Importantly, this randomized clinical trial confirms that inhibiting FAO using TMZ improves the prognosis of patients with HBV-related ACLF. In conclusion, this study provides a practical strategy for targeting metabolic reprogramming using TMZ to improve the survival of patients with HBV-related ACLF.

17.
Theranostics ; 10(5): 2029-2046, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089734

RESUMO

Metabolic syndrome (MTS) is a cluster of concurrent metabolic abnormal conditions. MTS and its component metabolic diseases are heterogeneous and closely related, making their relationships complicated, thus hindering precision treatment. Methods: We collected seven groups of samples (group a: healthy individuals; group b: obesity; group c: MTS; group d: hyperglycemia, group e: hypertension, group f: hyperlipidemia; group g: type II diabetes, n=7 for each group). We examined the molecular characteristics of each sample by metabolomic, proteomic and peptidomic profiling analysis. The differential molecules (including metabolites, proteins and peptides) between each disease group and the healthy group were recognized by statistical analyses. Furthermore, a two-step clustering workflow which combines multi-omics and clinical information was used to redefine molecularly and clinically differential groups. Meanwhile, molecular, clinical, network and pathway based analyses were used to identify the group-specific biological features. Results: Both shared and disease-specific molecular profiles among the six types of diseases were identified. Meanwhile, the patients were stratified into three distinct groups which were different from original disease definitions but presented significant differences in glucose and lipid metabolism (Group 1: relatively favorable metabolic conditions; Group 2: severe dyslipidemia; Group 3: dysregulated insulin and glucose). Group specific biological signatures were also systematically described. The dyslipidemia group showed higher levels in multiple lipid metabolites like phosphatidylserine and phosphatidylcholine, and showed significant up-regulations in lipid and amino acid metabolism pathways. The glucose dysregulated group showed higher levels in many polypeptides from proteins contributing to immune response. The another group, with better glucose/lipid metabolism ability, showed higher levels in lipid regulating enzymes like the lecithin cholesterol acyltransferase and proteins involved in complement and coagulation cascades. Conclusions: This multi-omics based study provides a general view of the complex relationships and an alternative classification for various metabolic diseases where the cross-talk or compensatory mechanism between the immune and metabolism systems plays a critical role.


Assuntos
Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Síndrome Metabólica/imunologia , Síndrome Metabólica/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glucose/metabolismo , Humanos , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Hipertensão/metabolismo , Insulina/metabolismo , Metabolismo dos Lipídeos , Masculino , Doenças Metabólicas/classificação , Síndrome Metabólica/classificação , Metabolômica/métodos , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/metabolismo , Peptidomiméticos , Fosfatidilcolinas/metabolismo , Fosfatidilserinas/metabolismo , Proteômica/métodos , Regulação para Cima
18.
Oncogene ; 39(3): 587-602, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31511647

RESUMO

Ubiquitin-specific-processing proteases (USPs), the largest deubiquitinating enzyme (DUB) subfamily, play critical roles in cancer. However, clinical utility of USPs is hindered by limited knowledge about their varied and substrate-dependent actions. Here, we performed a comprehensive investigation on pan-cancer impacts of USPs by integrating multi-omics data and annotated data resources, especially a deubiquitination network. Meaningful insights into the roles of 54 USPs in 29 types of cancers were generated. Although rare mutations were observed, a majority of USPs exhibited significant expressional alterations, prognostic impacts and strong correlations with cancer hallmark pathways. Notably, from our DUB-substrate interaction prediction model, additional USP-substrate interactions (USIs) were recognized to complement knowledge gap about cancer-relevant USIs. Intriguingly, expression signatures of the USIs revealed clinically meaningful cancer subtypes, where key USPs and substrates cooperatively contributed to significant prognosis differences among subtypes. Overall, this investigation provides a valuable resource to assist mechanism research and clinical utility about USPs.


Assuntos
Neoplasias/patologia , Proteases Específicas de Ubiquitina/metabolismo , Mineração de Dados , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Masculino , Modelos Biológicos , Mutação , Neoplasias/genética , Neoplasias/mortalidade , Prognóstico , Análise de Sobrevida , Ubiquitinação
19.
Se Pu ; 37(8): 887-896, 2019 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-31642260

RESUMO

Speckle type BTB/POZ protein (SPOP) is one of the most frequently mutated protein in prostate cancer. In this study, proteomics and metabolomics were integrated to study the effects of SPOP mutation on metabolism. First, LNCaP control (CON), SPOP wild-type (SPOP_WT), and SPOP mutation (SPOP_Y87N and SPOP_F133L) cells were subjected to a metabolomics study. The metabolomics data of LNCaP CON, SPOP_WT, SPOP_Y87N, and SPOP_F133L cells were evaluated by partial least squares-discriminant analysis (PLS-DA). Four groups could be clearly differentiated with an explanation ability of R2X=0.512, R2Y=0.616 and predictive ability of Q2=0.475. Totally, 36 differential metabolites were defined with variable importance for the projection (VIP) value > 1. Then, the 36 metabolites were subjected to one-way ANOVA analysis. Fumaric acid, malic acid, citric acid, aspartic acid, and asparagine were increased in LNCaP SPOP mutation cells compared to that in LNCaP SPOP_WT cells. Using a proteomics study, 909 differential proteins were found in LNCaP SPOP_Y87N and SPOP_F133L cells. MetaboAnalyst 3.0 was used to enrich metabolic pathways by using differential metabolites. KOBAS 3.0 was used to enrich metabolic pathways by using differential proteins. Both metabolomics and proteomics analysis showed that the tricarboxylic acid (TCA) cycle and aminoacyl-tRNA biosynthesis were significantly changed. To validate these findings, gas chromatography-mass spectrometry (GC-MS)-based metabolomics was performed in Du145 SPOP knock-out cells. The results indicated that the TCA cycle was activated in Du145 SPOP knock-out cells. Collectively, this study found that SPOP mutation significantly promoted TCA cycle in prostate cancer cells.


Assuntos
Domínio BTB-POZ , Metabolômica , Proteínas Nucleares/genética , Neoplasias da Próstata/genética , Proteômica , Proteínas Repressoras/genética , Linhagem Celular Tumoral , Ciclo do Ácido Cítrico , Humanos , Masculino , Redes e Vias Metabólicas , Mutação
20.
Oncol Rep ; 42(2): 745-752, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173261

RESUMO

The present study was designed to identify the endogenous RNA regulatory networks involved in hepatocellular carcinoma (HCC) by bioinformatic analysis. Both miRNA interaction network­based correlation analysis and expression­based Spearman correlation coefficients were utilized to identify potential mRNA­lncRNA interactions. Then, a competitive endogenous (ce)RNA network was constructed from these interactions, and network topology and Gene Ontology enrichment analyses were conducted to mine potential functions of ceRNAs. In HCC samples, a ceRNA network was constructed. It was composed of 35,657 edges connecting 113 lncRNAs and 6,136 mRNAs which were differentially expressed in HCC and normal liver tissues. Meanwhile, a number of significantly positively correlated mRNA and lncRNA pairs in this ceRNA network were found to be consistently positively correlated in another independent dataset. To be noted, further analyses on the potential roles of ceRNAs demonstrated than various lncRNAs such as LINC00657, TUG1 and SNHG1 may play key roles in HCC by regulating protein phosphorylation or cell cycle pathways or influencing miRNAs. From the perspective that lncRNAs can function as ceRNAs, this study revealed that the interaction between lncRNAs, miRNAs and mRNAs may provide new insight for the diagnosis and treatment in the tumorigenesis of hepatocellular carcinoma.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala/métodos , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Prognóstico
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