RESUMEN
N-Nitrosamine disinfection by-products (NAs-DBPs) have been well proven for its role in esophageal carcinogenesis. However, the role of intratumoral microorganisms in esophageal squamous cell carcinoma (ESCC) has not yet been well explored in the context of exposure to NAs-DBPs. Here, the multi-omics integration reveals F. periodonticum (Fp) as "facilitators" is highly enriched in cancer tissues and promotes the epithelial mesenchymal transition (EMT)-like subtype formation of ESCC. We demonstrate that Fp potently drives de novo synthesis of fatty acids, migration, invasion and EMT phenotype through its unique FadAL adhesin. However, N-nitrosomethylbenzylamine upregulates the transcription level of FadAL. Mechanistically, co-immunoprecipitation coupled to mass spectrometry shows that FadAL interacts with FLOT1. Furthermore, FLOT1 activates PI3K-AKT/FASN signaling pathway, leading to triglyceride and palmitic acid (PA) accumulation. Innovatively, the results from the acyl-biotin exchange demonstrate that FadAL-mediated PA accumulation enhances Wnt3A palmitoylation on a conserved cysteine residue, Cys-77, and promotes Wnt3A membrane localization and the translocation of ß-catenin into the nucleus, further activating Wnt3A/ß-catenin axis and inducing EMT phenotype. We therefore propose a "microbiota-cancer cell subpopulation" interaction model in the highly heterogeneous tumor microenvironment. This study unveils a mechanism by which Fp can drive ESCC and identifies FadAL as a potential diagnostic and therapeutic target for ESCC.
Asunto(s)
Transición Epitelial-Mesenquimal , Carcinoma de Células Escamosas de Esófago , Nitrosaminas , Proteína Wnt3A , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Proteína Wnt3A/metabolismo , Proteína Wnt3A/genética , Nitrosaminas/metabolismo , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/microbiología , Carcinoma de Células Escamosas de Esófago/genética , Línea Celular Tumoral , Lipoilación , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Animales , Ratones , Movimiento Celular/efectos de los fármacos , Transducción de SeñalRESUMEN
BACKGROUND: The cancer microbiota was considered the main risk factor for cancer progression. We had proved that Fusobacterium periodonticum (F.p) was higher abundance in Esophageal cancer(EC)tissues. Bioinformation analysis found that BCT was a key virulence protein of F.p. However, little is known about the role and mechanism of BCT in EC. This study aimed to recognize the key virulence protein of F.p and explore the mechanism of BCT in promoting EC. METHODS: We constructed a eukaryotic expression vector and purified the recombinant protein BCT. CCK8 used to analyzed the activity of EC after treated by different concentration of BCT. UPLC-MS/MS and ELISA used to detect the metabonomics and metabolites. The ability of migration and invasion was completed by transwell assay. RT-QPCR, WB used to analyze the expression of relevant genes. RESULTS: Our data showed that BCT was higher expression in EC tumor tissues (p < 0.05) and BCT in 20 µg/mL promoted the survival, invasion and migration of EC cells (EC109) (p < 0.05). Meanwhile, UPLC-MS/MS results suggested that BCT resulted in an augmentation of hypotaurine metabolism, arachidonic acid metabolism, glycolysis/gluconeogenesis, tryptophan metabolism, citrate cycle activity in EC109. The metabolic changes resulted in decreasing in glucose and pyruvate levels but increase in lactate dehydrogenase (LDH) activity and lactic acid (LA) as well as the expression of glucose transporter 1, Hexokinase 2, LDH which regulated the glycolysis were all changed (p < 0.05). The BCT treatment upregulated the expression of TLR4, Akt, HIF-1α (p < 0.05) which regulated the production of LA. Furthermore, LA stimulation promoted the expression of GPR81, Wnt, and ß-catenin (p < 0.05), thereby inducing EMT and metastasis in EC109 cells. CONCLUSION: Altogether, these findings identified that impact of BCT in regulation of glycolysis in EC109 and its involves the TLR4/Akt/HIF-1α pathway. Meanwhile, glycolysis increasing the release of LA and promote the EMT of EC109 by GPR81/Wnt/ß-catenin signaling pathway. In summary, our findings underscore the potential of targeting BCT as an innovative strategy to mitigate the development of EC.
Asunto(s)
Movimiento Celular , Transición Epitelial-Mesenquimal , Neoplasias Esofágicas , Fusobacterium , Glucosa , Ácido Láctico , Humanos , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Ácido Láctico/metabolismo , Línea Celular Tumoral , Glucosa/metabolismo , Fusobacterium/metabolismo , Proteínas Bacterianas/metabolismo , Invasividad Neoplásica , Regulación Neoplásica de la Expresión GénicaRESUMEN
Previous studies have shown the role of bacterial lipopolysaccharide (LPS) in promoting tumor progression. Our previous study found that the community richness of LPS-producing bacteria was significantly increased in the fresh stool samples of esophageal cancer (EC) patients, but the relative LPS levels and underlying mechanism in EC progression remain unknown. In this study, an case-control study found that the content of LPS was higher in serum of EC patients. Functional experiments of CCK8 assay and transwell assay showed that LPS contributed to the proliferation, migration, invasion of EC109 cells. Meanwhile, LPS induced EC109 to secrete IL-6 and TGF-ß1. Western blot analysis revealed the level of TLR4 and NF-κB increased significantly after LPS treatment. Epithelial marker E-cadherin was significantly down-regulated and interstitial marker N-cadherin and Vimentin were up-regulated after LPS treatment. However, TAK242 (TLR4 inhibitor) or PDTC (NF-κB inhibitor) could eliminate the inflammatory and EMT-promoting effects of LPS. In total, our results suggested that LPS exacerbated to the migration, invasion, and epithelial-mesenchymal transition of EC109 cells by TLR4/NF-κB axis. High level LPS may have a critical effect on the occurrence and development of EC.
Asunto(s)
Neoplasias Esofágicas , FN-kappa B , Humanos , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Receptor Toll-Like 4 , Transición Epitelial-Mesenquimal , Transducción de Señal , Estudios de Casos y Controles , Movimiento CelularRESUMEN
AIM: The effects of e-cigarettes on endothelial function remained controversial. The study aimed to investigate the effects of e-cigarettes on vascular endothelial function. METHODS AND RESULTS: PubMed, Web of Science, Embase, and Cochrane Library were searched up to December 2021. We only included the studies in which the control group included vaping without nicotine and tobacco. Pairwise and network meta-analyses were conducted for flow-mediated dilation (FMD), pulse wave velocity (PWV), and heart rate corrected augmentation index (AIx75). Eight studies involving 372 participants were eligible for this review. Compared with vaping without nicotine, e-cigarettes significantly increase in PWV (mean difference = 3.09; 95% confidential interval: 1.51-4.68, P < 0.001) and AIx75 (mean difference = 2.11; 95% confidential interval: 1.02-3.21, P < 0.001) indicators, but not affect FMD (mean difference = 0.78; 95% confidential interval: -0.08 to 1.64, P = 0.075). But compared with traditional tobacco, e-cigarettes did not affect FMD (mean difference = 0.28, 95% confidential interval: -0.45 to 0.59, P = 0.084). According to surface under the cumulative ranking curve (SUCRA), the e-cigarette ranked first for FMD (SUCRA = 97%), tobacco ranked first for PWV (SUCRA = 75%), and AIx75 (SUCRA = 99%). CONCLUSION: In summary, evidence from our pooled analyses indicated that acute inhalation of e-cigarettes leads to negative changes in vascular endothelial function. E-cigarettes cannot be used as an alternative to public health strategies for tobacco control and should not be considered cardiovascular safety products. More future research should be conducted to verify our findings.
Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Vapeo , Humanos , Nicotina/efectos adversos , Análisis de la Onda del Pulso , Ensayos Clínicos Controlados Aleatorios como Asunto , Vapeo/efectos adversosRESUMEN
Sewage treatment plants are an essential source of antibiotics, antibiotic resistance determinants, and bacteria in environmental waters. However, it is still unclear whether they can maintain a relatively stable relationship in wastewater and environmental waters. This study analyzed the removal capacity of the above three pollutants in the sewage treatment plant in summer and their impact on environmental waters, and then examines the relationship between the three contaminants in the wastewater and environmental waters in summer and winter based on our previous study. The results found that the removal capacity of bacteria in summer was poor, the concentration of fluoroquinolone in the effluent was higher than that in influent, and the abundance of intI1, tetW, qnrB, and ermB increased after wastewater treatment. Proteobacteria and Bacteroides were the main bacteria that constitute the correlation network between bacteria, and they existed stably in summer and winter. However, fluoroquinolones occupied a significant position in the determinant network of antibiotics and antibiotic resistance in summer and winter. There are fewer correlation between antibiotics and antibiotics resistance determinants in winter. Interestingly, the relationship between bacteria, antibiotics, and antibiotic resistance determinants was a mainly positive correlation in summer and negative correlation in winter. This study analyzed the relationship between bacteria, antibiotics, and antibiotic resistance determinants that were stable in the wastewater and environmental waters and pointed out the direction for subsequent targeted seasonal control of novel pollutants in wastewater and environmental waters.
Asunto(s)
Contaminantes Químicos del Agua , Purificación del Agua , Antibacterianos/análisis , Antibacterianos/farmacología , Bacterias/genética , Farmacorresistencia Microbiana , Genes Bacterianos , Estaciones del Año , Aguas del Alcantarillado/microbiología , Aguas Residuales/análisis , Agua , Contaminantes Químicos del Agua/análisis , Purificación del Agua/métodosRESUMEN
It was previously believed that the microbial community in the esophagus was relatively stable, but it has been reported that different esophageal diseases have different microbial community characteristics. In this study, we recruited patients with esophageal squamous cell carcinoma (ESCC) and collected 51 pairs of tumor and adjacent non-tumor tissues for full-length 16S rDNAsequencing and qPCR to compare the differences in microbial community structure. The results of sequencing in 19 pairs of tissues showed that Proteobacteria, Firmicutes, Bacteroidetes, Deinococcus-Thermus, and Actinobacteria were the main bacteria in tumor and adjacent non-tumor tissues. At the genus level, the bacteria with the highest relative proportion in tumor and adjacent non-tumor tissues were Streptococcus and Labrys, respectively. At the same time, it was observed that the complexity of microbial interactions in tumor tissues was weaker than that of adjacent non-tumor tissues. The results also found that the relative abundance of 24 taxa was statistically different between tumor and adjacent non-tumor tissues. The findings of qPCR in 32 pairs of tissues further evidence that the relative proportions of Blautia, Treponema, Lactobacillus murinus, Peptoanaerobacter stomatis, and Fusobacteria periodonticum were statistically different in tumor and adjacent non-tumor tissues. The findings of PIRCUSt2 indicated the lipopolysaccharide biosynthesis and biotin metabolism in the microbiome of cancer tissues are more significant. This study supplements the existing information on the structure, function, and interaction of microorganisms in the esophagus in situ and provides a direction for the further exploration of the relationship between esophageal in situ microorganisms and esophageal squamous cell carcinoma. KEY POINTS: ⢠The structure of the microbial community in esophageal cancer tissue and adjacent non-tumor tissues at the phylum level is similar ⢠Streptococcus and Labrys are the most important bacteria in esophageal tumor tissues and adjacent non-tumor tissues, respectively ⢠Microbial interactions in tumor tissues are stronger than in adjacent non-tumor tissues.