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Objective: Maintenance hemodialysis (MHD) patients suffer from enormous physical, mental stress and poor quality of life, so an increasing number of patients are in a long-term state of depression. A prominent feature of MHD patients is chronic persistent inflammation, which is also an important mechanism for the onset of depression. Therefore, finding economically convenient inflammatory markers to predict and diagnose the onset of depression in MHD patients is of great value. As a novel inflammatory marker, systemic immune inflammation index (SII) can more comprehensively reflect the inflammation and immunity level of patients. This study aims to explore the relationship between SII and depressive symptoms in MHD patients. Methods: A cross-sectional study was conducted on 206 MHD patients from three dialysis centers. Based on the Hospital Anxiety and Depression Scale (HADS) scores, patients were divided into non-depression and depression groups. Inter group comparison and multivariate logistic regression analysis were performed to determine whether SII is an independent risk factor for depression in MHD patients. Receiver operating characteristic (ROC) curve was used to evaluate the predictive value of SII on depression symptoms in MHD patients. Results: According to the HADS scale score, 38.83% of the included patients were in a state of depression. After adjusting for all confounding factors, MHD patients with SII>963.93 had a 4.709 times higher risk of depression than those with SII ≤ 478.32 (OR=4.709, 95% CI 1.821-12.178, P<0.01). ROC analysis showed that SII>685.11 was the best cutoff value for MHD depression patients, and the area under the curve (AUC) was 0.681. Conclusions: High SII is an independent risk factor for depressed MHD patients and an ideal inflammatory marker for predicting and identifying depression in MHD patients as assessed by the HADS scale.
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Colorectal cancer is a predominant malignancy with a second mortality worldwide. Despite its prevalence, therapeutic options remain constrained and surgical operation is still the most useful therapy. In this regard, a comprehensive spatially resolved quantitative proteome atlas was constructed to explore the functional proteomic landscape of colorectal cancer. This strategy integrates histopathological analysis, laser capture microdissection, and proteomics. Spatial proteome profiling of 200 tissue section samples facilitated by the fully integrated sample preparation technology SISPROT enabled the identification of more than 4000 proteins on the Orbitrap Exploris 240 from 2 mm2 × 10 µm tissue sections. Compared with normal adjacent tissues, we identified a spectrum of cancer-associated proteins and dysregulated pathways across various regions of colorectal cancer including ascending colon, transverse colon, descending colon, sigmoid colon, and rectum. Additionally, we conducted proteomic analysis on tumoral epithelial cells and paracancerous epithelium from early to advanced stages in hallmark rectum cancer and sigmoid colon cancer. Bioinformatics analysis revealed functional proteins and cell-type signatures associated with different regions of colorectal tumors, suggesting potential clinical implications. Overall, this study provides a comprehensive spatially resolved functional proteome landscape of colorectal cancer, serving as a valuable resource for exploring potential biomarkers and therapeutic targets.
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Neoplasias Colorretais , Proteoma , Proteômica , Microambiente Tumoral , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Proteômica/métodos , Proteoma/análise , Microdissecção e Captura a Laser , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Biologia ComputacionalRESUMO
Type 2 diabetes mellitus (T2DM) is a common comorbidity among Parkinson's disease (PD) patients. Yet, little is known about dysregulated pathways that are unique in PD patients with T2DM. We applied high-resolution metabolomic profiling in serum samples of 636 PD and 253 non-PD participants recruited from Central California. We conducted an initial discovery metabolome-wide association and pathway enrichment analysis. After adjusting for multiple testing, in positive (or negative) ion mode, 30 (25) metabolic features were associated with T2DM in both PD and non-PD participants, 162 (108) only in PD participants, and 32 (7) only in non-PD participants. Pathway enrichment analysis identified 17 enriched pathways associated with T2DM in both the PD and non-PD participants, 26 pathways only in PD participants, and 5 pathways only in non-PD participants. Several amino acid, nucleic acids, and fatty acid metabolisms were associated with T2DM only in the PD patient group suggesting a possible link between PD and T2DM.
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It has been suggested that gut microbiota influence Parkinson's disease (PD) via the gut-brain axis. Here, we examine associations between diet and gut microbiome composition and its predicted functional pathways in patients with PD. We assessed gut microbiota in fecal samples from 85 PD patients in central California using 16S rRNA gene sequencing. Diet quality was assessed by calculating the Healthy Eating Index 2015 (HEI-2015) based on the Diet History Questionnaire II. We examined associations of diet quality, fiber, and added sugar intake with microbial diversity, composition, taxon abundance, and predicted metagenomic profiles, adjusting for age, sex, race/ethnicity, and sequencing platform. Higher HEI scores and fiber intake were associated with an increase in putative anti-inflammatory butyrate-producing bacteria, such as the genera Butyricicoccus and Coprococcus 1. Conversely, higher added sugar intake was associated with an increase in putative pro-inflammatory bacteria, such as the genera Klebsiella. Predictive metagenomics suggested that bacterial genes involved in the biosynthesis of lipopolysaccharide decreased with higher HEI scores, whereas a simultaneous decrease in genes involved in taurine degradation indicates less neuroinflammation. We found that a healthy diet, fiber, and added sugar intake affect the gut microbiome composition and its predicted metagenomic function in PD patients. This suggests that a healthy diet may support gut microbiome that has a positive influence on PD risk and progression.
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BACKGROUND: Organophosphorus pesticides (OP) have been associated with various human health conditions. Animal experiments and in-vitro models suggested that OP may also affect the gut microbiota. We examined associations between ambient chronic exposure to OP and gut microbial changes in humans. METHODS: We recruited 190 participants from a community-based epidemiologic study of Parkinson's disease living in a region known for heavy agricultural pesticide use in California. Of these, 61% of participants had Parkinson's disease and their mean age was 72 years. Microbiome and predicted metagenome data were generated by 16S rRNA gene sequencing of fecal samples. Ambient long-term OP exposures were assessed using pesticide application records combined with residential addresses in a geographic information system. We examined gut microbiome differences due to OP exposures, specifically differences in microbial diversity based on the Shannon index and Bray-Curtis dissimilarities, and differential taxa abundance and predicted Metacyc pathway expression relying on regression models and adjusting for potential confounders. RESULTS: OP exposure was not associated with alpha or beta diversity of the gut microbiome. However, the predicted metagenome was sparser and less evenly expressed among those highly exposed to OP (p = 0.04). Additionally, we found that the abundance of two bacterial families, 22 genera, and the predicted expression of 34 Metacyc pathways were associated with long-term OP exposure. These pathways included perturbed processes related to cellular respiration, increased biosynthesis and degradation of compounds related to bacterial wall structure, increased biosynthesis of RNA/DNA precursors, and decreased synthesis of Vitamin B1 and B6. CONCLUSION: In support of previous animal studies and in-vitro findings, our results suggest that ambient chronic OP pesticide exposure alters gut microbiome composition and its predicted metabolism in humans.
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Microbioma Gastrointestinal , Microbiota , Doença de Parkinson , Praguicidas , Idoso , Humanos , Bactérias , Compostos Organofosforados , Praguicidas/efeitos adversos , RNA Ribossômico 16S/genéticaRESUMO
BACKGROUND: Colorectal Cancer (CRC) is a prevalent form of cancer, and the effectiveness of the main postoperative chemotherapy treatment, FOLFOX, varies among patients. In this study, we aimed to identify potential biomarkers for predicting the prognosis of CRC patients treated with FOLFOX through plasma proteomic characterization. METHODS: Using a fully integrated sample preparation technology SISPROT-based proteomics workflow, we achieved deep proteome coverage and trained a machine learning model from a discovery cohort of 90 CRC patients to differentiate FOLFOX-sensitive and FOLFOX-resistant patients. The model was then validated by targeted proteomics on an independent test cohort of 26 patients. RESULTS: We achieved deep proteome coverage of 831 protein groups in total and 536 protein groups in average for non-depleted plasma from CRC patients by using a Orbitrap Exploris 240 with moderate sensitivity. Our results revealed distinct molecular changes in FOLFOX-sensitive and FOLFOX-resistant patients. We confidently identified known prognostic biomarkers for colorectal cancer, such as S100A4, LGALS1, and FABP5. The classifier based on the biomarker panel demonstrated a promised AUC value of 0.908 with 93% accuracy. Additionally, we established a protein panel to predict FOLFOX effectiveness, and several proteins within the panel were validated using targeted proteomic methods. CONCLUSIONS: Our study sheds light on the pathways affected in CRC patients treated with FOLFOX chemotherapy and identifies potential biomarkers that could be valuable for prognosis prediction. Our findings showed the potential of mass spectrometry-based proteomics and machine learning as an unbiased and systematic approach for discovering biomarkers in CRC.
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Objective: To compare the intervention effects and pharmacoeconomic advantages of Fufang Huangbai Fluid (FFHB) hydropathic compress versus Antimicrobial Calcium Alginate Wound Dressing (ACAWD) in the treatment of diabetic foot infections (DFI). Methods: Patients with DF who were hospitalized in the peripheral vascular Department of Dongzhimen Hospital of Beijing University of Chinese Medicine from December 2020 to February 2022 and met the inclusion and excluding criteria were allocated into the experimental group and control group through minimization randomization. The experimental group was treated with FFHB hydropathic compress for 2 weeks, while the control group was treated with ACAWD for the same duration. The wound healing of both groups was monitored for 1 month post-discharge. Clinical data from all eligible patients were collected, and differences in various indices between cohorts were analyzed. Results: 22 in the experimental group (including two fell off) and 20 in the control group. After the treatment, the negative rate of wound culture in the experimental group was 30% and that in the control group was 10%, There was no significant difference in the negative rate of wound culture and change trend of minimum inhibitory concentration (MIC) value of drug sensitivity (p > 0.05). The infection control rate of the experimental group was 60%, and that of the control group was 25%. The difference between the two groups was statistically significant (χ2 = 5.013, p = 0.025). The median wound healing rate of the experimental group was 34.4% and that of the control group was 33.3%. There was no significant difference between the two groups (p > 0.05). During the follow-up 1 month later, the wound healing rate in the experimental group was higher, and the difference was statistically significant (p = 0.047). Pharmacoeconomic evaluations indicated that the experimental group had greater cost-effectiveness compared to the control group. Conclusion: In the preliminary study, FFHB demonstrated comparable pathogenic and clinical efficacy to ACAWD in the treatment of mild DF infection, and exhibited superior pharmacoeconomic advantages. With the aid of infection control, the wound healing rate in the FFHB group showed notable improvement. Nevertheless, due to the limited sample size, larger-scale studies are warranted to further validate these findings. Clinical Trial Registration: (https://www.chictr.org.cn/showproj.aspx?proj=66175), identifier (ChiCTR2000041443).
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Visualizing synaptic connectivity has traditionally relied on time-consuming electron microscopy-based imaging approaches. To scale the analysis of synaptic connectivity, fluorescent protein-based techniques have been established, ranging from the labeling of specific pre- or post-synaptic components of chemical or electrical synapses to transsynaptic proximity labeling technology such as GRASP and iBLINC. In this paper, we describe WormPsyQi, a generalizable image analysis pipeline that automatically quantifies synaptically localized fluorescent signals in a high-throughput and robust manner, with reduced human bias. We also present a resource of 30 transgenic strains that label chemical or electrical synapses throughout the nervous system of the nematode Caenorhabditis elegans, using CLA-1, RAB-3, GRASP (chemical synapses), or innexin (electrical synapse) reporters. We show that WormPsyQi captures synaptic structures in spite of substantial heterogeneity in neurite morphology, fluorescence signal, and imaging parameters. We use these toolkits to quantify multiple obvious and subtle features of synapses - such as number, size, intensity, and spatial distribution of synapses - in datasets spanning various regions of the nervous system, developmental stages, and sexes. Although the pipeline is described in the context of synapses, it may be utilized for other 'punctate' signals, such as fluorescently tagged neurotransmitter receptors and cell adhesion molecules, as well as proteins in other subcellular contexts. By overcoming constraints on time, sample size, cell morphology, and phenotypic space, this work represents a powerful resource for further analysis of synapse biology in C. elegans.
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Caenorhabditis elegans , Sinapses Elétricas , Humanos , Animais , Animais Geneticamente Modificados , Corantes , FluorescênciaRESUMO
BACKGROUND: Prior studies suggested that air pollution exposure may increase the risk of Parkinson's Disease (PD). We investigated the long-term impacts of traffic-related and multiple sources of particulate air pollution on PD in central California. METHODS: Our case-control analysis included 761 PD patients and 910 population controls. We assessed exposure at residential and occupational locations from 1981 to 2016, estimating annual average carbon monoxide (CO) concentrations - a traffic pollution marker - based on the California Line Source Dispersion Model, version 4. Additionally, particulate matter (PM2.5) concentrations were based on a nationwide geospatial chemical transport model. Exposures were assessed as 10-year averages with a 5-year lag time prior to a PD diagnosis for cases and an interview date for controls, subsequently categorized into tertiles. Logistic regression models were used, adjusting for various factors. RESULTS: Traffic-related CO was associated with an increased odds ratio for PD at residences (OR for T3 vs. T1: 1.58; 95% CI: 1.20, 2.10; p-trend = 0.02) and workplaces (OR for T3 vs. T1: 1.91; 95% CI: 1.22, 3.00; p-trend <0.01). PM2.5 was also positively associated with PD at residences (OR for T3 vs. T1: 1.62; 95% CI: 1.22, 2.15; p-trend <0.01) and workplaces (OR for T3 vs. T1: 1.85; 95% CI: 1.21, 2.85; p-trend <0.01). Associations remained robust after additional adjustments for smoking status and pesticide exposure and were consistent across different exposure periods. CONCLUSION: We found that long-term modeled exposure to local traffic-related air pollution (CO) and fine particulates from multiple sources (PM2.5) at homes and workplaces in central California was associated with an increased risk of PD.
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Poluentes Atmosféricos , Poluição do Ar , Doença de Parkinson , Poluição Relacionada com o Tráfego , Humanos , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise , Exposição Ambiental/análise , Doença de Parkinson/epidemiologia , Doença de Parkinson/etiologia , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Material Particulado/toxicidade , Material Particulado/análise , Poeira/análise , California/epidemiologiaRESUMO
BACKGROUND: Untargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands of metabolites. Metabolic networks based on these data can help uncover disease-related perturbations across interconnected pathways. OBJECTIVE: Identify metabolic disturbances associated with Parkinson's disease (PD) in two population-based studies using untargeted metabolomics. METHODS: We performed a metabolome-wide association study (MWAS) of PD using serum-based untargeted metabolomics data derived from liquid chromatography with high-resolution mass spectrometry (LC-HRMS) using two distinct population-based case-control populations. We also combined our results with a previous publication of 34 metabolites linked to PD in a large-scale, untargeted MWAS to assess external validation. RESULTS: LC-HRMS detected 4,762 metabolites for analysis (HILIC: 2716 metabolites; C18: 2046 metabolites). We identified 296 features associated with PD at FDR<0.05, 134 having a log2 fold change (FC) beyond ±0.5 (228 beyond ±0.25). Of these, 104 were independently associated with PD in both discovery and replication studies at p<0.05 (170 at p<0.10), while 27 were associated with levodopa-equivalent dose among the PD patients. Intriguingly, among the externally validated features were the microbial-related metabolites, p-cresol glucuronide (FC=2.52, 95% CI=1.67, 3.81, FDR=7.8e-04) and p-cresol sulfate. P-cresol glucuronide was also associated with motor symptoms among patients. Additional externally validated metabolites associated with PD include phenylacetyl-L-glutamine, trigonelline, kynurenine, biliverdin, and pantothenic acid. Novel associations include the anti-inflammatory metabolite itaconate (FC=0.79, 95% CI=0.73, 0.86; FDR=2.17E-06) and cysteine-S-sulfate (FC=1.56, 95% CI=1.39, 1.75; FDR=3.43E-11). Seventeen pathways were enriched, including several related to amino acid and lipid metabolism. CONCLUSIONS: Our results revealed PD-associated metabolites, confirming several previous observations, including for p-cresol glucuronide, and newly implicating interesting metabolites, such as itaconate. Our data also suggests metabolic disturbances in amino acid and lipid metabolism and inflammatory processes in PD.
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Aminoácidos , Doença de Parkinson , Humanos , Aminoácidos/metabolismo , Doença de Parkinson/metabolismo , Metabolismo dos Lipídeos , GlucuronídeosRESUMO
Cytonuclear disruption may accompany allopolyploid evolution as a consequence of the merger of different nuclear genomes in a cellular environment having only one set of progenitor organellar genomes. One path to reconcile potential cytonuclear mismatch is biased expression for maternal gene duplicates (homoeologs) encoding proteins that target to plastids and/or mitochondria. Assessment of this transcriptional form of cytonuclear coevolution at the level of individual cells or cell types remains unexplored. Using single-cell (sc-) and single-nucleus (sn-) RNAseq data from eight tissues in three allopolyploid species, we characterized cell type-specific variations of cytonuclear coevolutionary homoeologous expression and demonstrated the temporal dynamics of expression patterns across development stages during cotton fiber development. Our results provide unique insights into transcriptional cytonuclear coevolution in plant allopolyploids at the single-cell level.
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Mitocôndrias , Plastídeos , Mitocôndrias/genética , Diferenciação Celular , Núcleo SolitárioRESUMO
Background: Numerous studies have demonstrated that retinal chronic inflammation plays a critical role in the pathogenesis of diabetic macular edema (DME). However, studies about the association between peripheral complete blood count, an inexpensive and easily measurable laboratory index, and DME are limited. Research design and methods: The current study was a hospital-based, cross-sectional study. The participants were inpatients with type 2 diabetes who underwent vitrectomy for PDR, and the contralateral eyes in these PDR patients meeting the criteria were included in the study. Central macular thickness (CMT) was measured automatically and the DME was characterized as CMT ≥ 300 µm. Results: A total of 239 PDR participants were enrolled. The average age was 55.46 ± 10.08 years old, and the average CMT was 284.23 ± 122.09 µm. In the fully adjusted model, for CMT, the results revealed a significantly negative association between CMT and both white blood cell (WBC) count and neutrophil count (ß = -11.95, 95% CI: -22.08, -1.82; p = 0.0218; ß = -14.96, 95% CI: -28.02, -1.90; p = 0.0259, respectively); for DME, the results showed an inverse association between DME and WBC count, monocyte count, and eosinophil count (OR = 0.75, 95% CI: 0.59, 0.95; p = 0.0153; OR = 0.07, 95% CI: 0.00, 0.92; p = 0.0431; OR = 0.03, 95% CI: 0.00, 0.88; p = 0.0420, respectively). Conclusions: In conclusion, our results suggest that WBC and its subtypes in circulation may play an important role in the pathogenesis of DME in PDR patients.
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Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Edema Macular , Humanos , Pessoa de Meia-Idade , Idoso , Retinopatia Diabética/complicações , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/patologia , Edema Macular/etiologia , Edema Macular/patologia , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Tomografia de Coerência Óptica/métodos , Contagem de Células SanguíneasRESUMO
FOXA1, a transcription factor involved in epigenetic reprogramming, is crucial for breast cancer progression. However, the mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-linked ß-N-acetylglucosamine modification (O-GlcNAcylation) of FOXA1 promotes breast cancer metastasis by orchestrating the transcription of numerous metastasis regulators. O-GlcNAcylation at Thr432, Ser441, and Ser443 regulates the stability of FOXA1 and promotes its assembly with chromatin. O-GlcNAcylation shapes the FOXA1 interactome, especially triggering the recruitment of the transcriptional repressor methyl-CpG binding protein 2 and consequently stimulating FOXA1 chromatin-binding sites to switch to chromatin loci of adhesion-related genes, including EPB41L3 and COL9A2. Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes and thus inhibits breast cancer proliferation and metastasis both in vitro and in vivo. Our data establish the importance of aberrant FOXA1 O-GlcNAcylation in breast cancer progression and indicate that targeting O-GlcNAcylation is a therapeutic strategy for metastatic breast cancer.
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Neoplasias da Mama , Cromatina , Humanos , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Epigenômica , Proteínas dos MicrofilamentosRESUMO
INTRODUCTION: Parkinson's disease (PD) is now considered a systemic disease, and some phenotypes may be modifiable by diet. We will compare the diet quality and intake of specific nutrients and food groups of PD patients with household and community controls to examine how diet may influence PD clinical features. METHODS: We conducted a case-control study of 98 PD patients and 83 controls (household = 53; community = 30) in central California, assessing dietary habits over the past month and calculating the Healthy Eating Index (HEI)-2015. We employed multivariate logistic and linear regression analyses to assess associations between diet and PD status, PD symptom profiles, and medication, adjusting for relevant confounders. RESULTS: PD patients had a lower HEI score than controls, with an OR of 0.65 (95% CI: 0.45, 0.94) per 10-points increase in HEI. Lower-quality diet was characterized by higher intakes of carbohydrates, total and added sugars, and trans fats and lower intakes of fiber, folate, unsaturated fatty acids, protein, and fat. PD patients with chronic constipation had a 4.84 point lower HEI score than those without (ß per 10-point in HEI: -0.48; 95% CI: -0.97, -0.00). Furthermore, patients on high dopamine agonist doses consumed more sugar than those on lower doses. CONCLUSION: PD patients consume a lower-quality diet compared to household and community controls. Dietary modifications may alleviate non-motor symptoms like constipation, and promoting a healthy diet should become a part of routine care and disease management for PD patients, with special attention on agonist-treated and hyposmic patients.
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The diabetes-cancer association remains underexplained. Here, we describe a glucose-signaling axis that reinforces glucose uptake and glycolysis to consolidate the Warburg effect and overcome tumor suppression. Specifically, glucose-dependent CK2 O-GlcNAcylation impedes its phosphorylation of CSN2, a modification required for the deneddylase CSN to sequester Cullin RING ligase 4 (CRL4). Glucose, therefore, elicits CSN-CRL4 dissociation to assemble the CRL4COP1 E3 ligase, which targets p53 to derepress glycolytic enzymes. A genetic or pharmacologic disruption of the O-GlcNAc-CK2-CSN2-CRL4COP1 axis abrogates glucose-induced p53 degradation and cancer cell proliferation. Diet-induced overnutrition upregulates the CRL4COP1-p53 axis to promote PyMT-induced mammary tumorigenesis in wild type but not in mammary-gland-specific p53 knockout mice. These effects of overnutrition are reversed by P28, an investigational peptide inhibitor of COP1-p53 interaction. Thus, glycometabolism self-amplifies via a glucose-induced post-translational modification cascade culminating in CRL4COP1-mediated p53 degradation. Such mutation-independent p53 checkpoint bypass may represent the carcinogenic origin and targetable vulnerability of hyperglycemia-driven cancer.
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Neoplasias , Proteína Supressora de Tumor p53 , Animais , Camundongos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Glucose , Ubiquitina-Proteína Ligases/metabolismo , Carcinogênese/genética , Transformação Celular Neoplásica/genéticaRESUMO
Reversible and dynamic O-GlcNAcylation regulates vast networks of highly coordinated cellular and nuclear processes. Although dysregulation of the sole enzyme O-GlcNAc transferase (OGT) was shown to be associated with the progression of hepatocellular carcinoma (HCC), the mechanisms by which OGT controls the cis-regulatory elements in the genome and performs transcriptional functions remain unclear. Here, we demonstrate that elevated OGT levels enhance HCC proliferation and metastasis, in vitro and in vivo, by orchestrating the transcription of numerous regulators of malignancy. Diverse transcriptional regulators are recruited by OGT in HCC cells undergoing malignant progression, which shapes genome-wide OGT chromatin cis-element occupation. Furthermore, an unrecognized cooperation between ZNF263 and OGT is crucial for activating downstream transcription in HCC cells. We reveal that O-GlcNAcylation of Ser662 is responsible for the chromatin association of ZNF263 at candidate gene promoters and the OGT-facilitated HCC malignant phenotypes. Our data establish the importance of aberrant OGT activity and ZNF263 O-GlcNAcylation in the malignant progression of HCC and support the investigation of OGT as a therapeutic target for HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Cromatina/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , N-Acetilglucosaminiltransferases/genética , Proteínas de Ligação a DNA/genéticaRESUMO
The cGAS-STING pathway has long been recognized as playing a crucial role in immune surveillance and tumor suppression. Here, we show that when the pathway is activated in a cancer-cell-autonomous response manner, it confers drug resistance. Targeted or conventional chemotherapy drugs promoted cytosolic DNA accumulation in cancer cells, activating the cGAS-STING pathway and downstream TBK1-IRF3/NF-κB signaling. This cancer cell-intrinsic response enabled the cells to counteract drug stress, allowing treatment resistance to be acquired and maintained. Blockade of stimulator of interferon genes (STING) signaling delayed and overcame resistance in models in vitro and in vivo. This finding uncovers an alternative face of cGAS-STING signaling other than the well-reported modulation of microenvironmental immune cells. It also implies a caution for the combination of STING agonist with targeted or conventional chemotherapy drug treatment, a strategy prevailing in current clinical trials.
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Resistencia a Medicamentos Antineoplásicos , Proteínas de Membrana , Neoplasias , Nucleotidiltransferases , DNA/metabolismo , Neoplasias/tratamento farmacológico , NF-kappa B/metabolismo , Nucleotidiltransferases/metabolismo , Transdução de Sinais , Proteínas de Membrana/metabolismoRESUMO
[This corrects the article DOI: 10.7150/thno.35729.].
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DNA topoisomerase IIα (TOP2A) plays a vital role in replication and cell division by catalytically altering DNA topology. It is a prominent target for anticancer drugs, but clinical efficacy is often compromised due to chemoresistance. In this study, we investigate the role of TOP2A O-GlcNAcylation in breast cancer cells and patient tumor tissues. Our results demonstrate that elevated TOP2A, especially its O-GlcNAcylation, promotes breast cancer malignant progression and resistance to adriamycin (Adm). O-GlcNAcylation at Ser1469 enhances TOP2A chromatin DNA binding and catalytic activity, leading to resistance to Adm in breast cancer cells and xenograft models. Mechanistically, O-GlcNAcylation-modulated interactions between TOP2A and cell cycle regulators influence downstream gene expression and contribute to breast cancer drug resistance. These results reveal a previously unrecognized mechanistic role for TOP2A O-GlcNAcylation in breast cancer chemotherapy resistance and provide support for targeting TOP2A O-GlcNAcylation in cancer therapy.