RESUMO
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.
Assuntos
Movimento Celular , Transição Epitelial-Mesenquimal , Neoplasias Esofágicas , Fusobacterium , Glucose , Ácido Láctico , Humanos , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/metabolismo , Ácido Láctico/metabolismo , Linhagem Celular Tumoral , Glucose/metabolismo , Fusobacterium/metabolismo , Proteínas de Bactérias/metabolismo , Invasividade Neoplásica , Regulação Neoplásica da Expressão GênicaRESUMO
Intensified sanitation practices amid the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak might result in the increased release of chloramine disinfectants into surface water, significantly promoting the formation of nitrosamine disinfection by-products (DBPs) in drinking water. Unfortunately, these nitrosamine DBPs exhibit significant genotoxic, carcinogenic, and mutagenic properties, whereas chlorinating disinfectants remain in global practice. The current review provides valuable insights into the occurrence, identification, contamination status, exposure limits, and toxicity of the new unregulated disinfection by-products (nitrosamine DBPs) in drinking water. As a result, concentrations of nitrosamine DBPs far exceed allowable limits in drinking water, and prolonged exposure has the potential to cause metabolic disorders, a critical step in tumor initiation and progression. Importantly, based on recent research, we have concluded the role of nitrosamines DBPs in different metabolic pathways. Remarkably, nitrosamine DBPs can induce chronic inflammation and initiate tumors by activating sphingolipid and polyunsaturated fatty acid metabolism. Regarding amino acid and nucleotide metabolism, nitrosamine DBPs can inhibit tryptophan metabolism and de novo nucleotide synthesis. Moreover, inhibition of de novo nucleotide synthesis fails to repair DNA damage induced by nitrosamines. Additionally, the accumulation of lactate induced by nitrosamine DBPs may act as a pivotal signaling molecule in communication within the tumor microenvironment. However, with the advancement of tumor metabolomics, understanding the role of nitrosamine DBPs in causing cancer by inducing metabolic abnormalities significantly lags behind, and specific mechanisms of toxic effects are not clearly defined. Urgently, further studies exploring this promising area are needed.
Assuntos
Desinfetantes , Água Potável , Neoplasias , Nitrosaminas , Humanos , Nitrosaminas/toxicidade , Desinfetantes/toxicidade , Neoplasias/induzido quimicamente , Neoplasias/metabolismo , Poluentes Químicos da Água/toxicidade , Animais , Desinfecção , Purificação da Água , COVID-19 , Carcinógenos/toxicidadeRESUMO
INTRODUCTION: Small cell lung cancer (SCLC) is prone to chemoresistance, which is closely related to genome homeostasis-related processes, such as DNA damage and repair. Nucleophagy is the elimination of specific nuclear substances by cells themselves and is responsible for maintaining genome and chromosome stability. However, the roles of nucleophagy in tumour chemoresistance have not been investigated. OBJECTIVES: The aim of this work was to elucidate the mechanism of chemoresistance in SCLC and reverse this chemoresistance. METHODS: RNA-seq data from SCLC cohorts, chemosensitive SCLC cells and the corresponding chemoresistant cells were used to discover genes associated with chemoresistance and patient prognosis. In vitro and in vivo experiments were performed to verify the effect of high-mobility group box 1 (HMGB1) knockdown or overexpression on the chemotherapeutic response in SCLC. The regulatory effect of HMGB1 on nucleophagy was then investigated by coimmunoprecipitation (co-IP) and mass spectrometry (MS), and the underlying mechanism was explored using pharmacological inhibitors and mutant proteins. RESULTS: HMGB1 is a factor indicating poor prognosis and promotes chemoresistance in SCLC. Mechanistically, HMGB1 significantly increases PARP1-LC3 binding to promote nucleophagy via PARP1 PARylation, which leads to PARP1 turnover from DNA lesions and chemoresistance. Furthermore, chemoresistance in SCLC can be attenuated by blockade of the PARP1-LC3 interaction or PARP1 inhibitor (PARPi) treatment. CONCLUSIONS: HMGB1 can induce PARP1 self-modification, which promotes the interaction of PARP1 with LC3 to promote nucleophagy and thus chemoresistance in SCLC. HMGB1 could be a predictive biomarker for the PARPi response in patients with SCLC. Combining chemotherapy with PARPi treatment is an effective therapeutic strategy for overcoming SCLC chemoresistance.
RESUMO
In recent decades, with the continuous development of high-throughput sequencing technology, data volume in medical research has increased, at the same time, almost all clinical researchers have their own independent omics data, which provided a better condition for data mining and a deeper understanding of gene functions. However, for these large amounts of data, many common and cutting-edge effective bioinformatics research methods still cannot be widely used. This has encouraged the establishment of many analytical platforms, a portion of databases or platforms were designed to solve the special analysis needs of users, for instance, MG RAST, IMG/M, Qiita, BIGSdb, and TRAPR were developed for specific omics research, and some databases or servers provide solutions for special problems solutions. Metascape was designed to only provide functional annotations of genes as well as function enrichment analysis; BioNumerics and RidomSeqSphere+ perform multilocus sequence typing; CARD provides only antimicrobial resistance annotations. Additionally, some web services are outdated, and inefficient interaction often fails to meet the needs of researchers, such as our previous versions of the platform. Therefore, the demand to complete massive data processing tasks urgently requires a comprehensive bioinformatics analysis platform. Hence, we have developed a website platform, Sangerbox 3.0 (http://vip.sangerbox.com/), a web-based tool platform. On a user-friendly interface that also supports differential analysis, the platform provides interactive customizable analysis tools, including various kinds of correlation analyses, pathway enrichment analysis, weighted correlation network analysis, and other common tools and functions, users only need to upload their own corresponding data into Sangerbox 3.0, select required parameters, submit, and wait for the results after the task has been completed. We have also established a new interactive plotting system that allows users to adjust the parameters in the image; moreover, optimized plotting performance enables users to adjust large-capacity vector maps on the web site. At the same time, we have integrated GEO, TCGA, ICGC, and other databases and processed data in batches, greatly reducing the difficulty to obtain data and improving the efficiency of bioimformatics study for users. Finally, we also provide users with rich sources of bioinformatics analysis courses, offering a platform for researchers to share and exchange knowledge.