RESUMEN
BACKGROUND & AIMS: Most patients with gastric cancer (GCa) are diagnosed at an advanced stage. We aimed to investigate novel fecal signatures for clinical application in early diagnosis of GCa. METHODS: This was an observational study that included 1043 patients from 10 hospitals in China. In the discovery cohort, 16S ribosomal RNA gene analysis was performed in paired samples (tissues and feces) from patients with GCa and chronic gastritis (ChG) to determine differential abundant microbes. Their relative abundances were detected using quantitative real-time polymerase chain reaction to test them as bacterial candidates in the training cohort. Their diagnostic efficacy was validated in the validation cohort. RESULTS: Significant enrichments of Streptococcus anginosus (Sa) and Streptococcus constellatus (Sc) in GCa tumor tissues (P < .05) and feces (P < .0001) were observed in patients with intraepithelial neoplasia, early and advanced GCa. Either the signature parallel test SaâªSc or single signature Sa/Sc demonstrated superior sensitivity (Sa: 75.6% vs 72.1%, P < .05; Sc: 84.4% vs 64.0%, P < .001; and SaâªSc: 91.1% vs 81.4%, P < .01) in detecting early GCa compared with advanced GCa (specificity: Sa: 84.0% vs 83.9%, Sc: 70.4% vs 82.3%, and SaâªSc: 64.0% vs 73.4%). Fecal signature SaâªSc outperformed SaâªCEA/ScâªCEA in the discrimination of advanced GCa (sensitivity: 81.4% vs 74.2% and 81.4% vs 72.3%, P < .01; specificity: 73.4% vs 81.0 % and 73.4% vs 81.0%). The performance of SaâªSc in the diagnosis of both early and advanced GCa was verified in the validation cohort. CONCLUSION: Fecal Sa and Sc are noninvasive, accurate, and sensitive signatures for early warning in GCa. (ClinicalTrials.gov, Number: NCT04638959).
Asunto(s)
Neoplasias Gástricas , Streptococcus constellatus , Detección Precoz del Cáncer , Heces , Humanos , Neoplasias Gástricas/diagnóstico , Streptococcus anginosus/genética , Streptococcus constellatus/genéticaRESUMEN
BACKGROUND: Colorectal cancer (CRC) incidence has increased among patients aged <50 years. Exploring high-risk factors and screening high-risk populations may help lower early-onset CRC (EO-CRC) incidence. We developed noninvasive predictive models for EO-CRC and investigated its risk factors. METHODS: This retrospective multicenter study collected information on 1756 patients (811 patients with EO-CRC and 945 healthy controls) from two medical centers in China. Sociodemographic features, clinical symptoms, medical and family history, lifestyle, and dietary factors were measured. Patients from one cohort were randomly assigned (8:2) to two groups for model establishment and internal validation, and another independent cohort was used for external validation. Multivariable logistic regression, random forest, and eXtreme Gradient Boosting (XGBoost) were performed to establish noninvasive predictive models for EO-CRC. Some variables in the model influenced EO-CRC occurrence and were further analyzed. Multivariable logistic regression analysis yielded adjusted odd ratios (ORs) and 95% confidence intervals (CIs). RESULTS: All three models showed good performance, with areas under the receiver operator characteristic curves (AUCs) of 0.82, 0.84, and 0.82 in the internal and 0.78, 0.79, and 0.78 in the external validation cohorts, respectively. Consumption of sweet (OR 2.70, 95% CI 1.89-3.86, P < 0.001) and fried (OR 2.16, 95% CI 1.29-3.62, P < 0.001) foods ≥3 times per week was significantly associated with EO-CRC occurrence. CONCLUSION: We established noninvasive predictive models for EO-CRC and identified multiple nongenetic risk factors, especially sweet and fried foods. The model has good performance and can help predict the occurrence of EO-CRC in the Chinese population.
Asunto(s)
Neoplasias Colorrectales , Estilo de Vida , Humanos , Pueblo Asiatico , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/etiología , Estudios Retrospectivos , Factores de Riesgo , Distribución AleatoriaRESUMEN
OBJECTIVE: Microbiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation between the gut microbiota and glucose metabolism is unknown in CRC. DESIGN: 18F-FDG (18F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in Fusobacterium (F.) nucleatum-induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1. RESULTS: We have found F. nucleatum abundance correlated with high glucose metabolism in patients with CRC. Furthermore, F. nucleatum supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically, F. nucleatum activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function. CONCLUSION: F. nucleatum and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated F. nucleatum.
Asunto(s)
Carcinogénesis/genética , Neoplasias Colorrectales/genética , Infecciones por Fusobacterium/genética , Glucólisis/genética , ARN Largo no Codificante/genética , Animales , Biomarcadores de Tumor , Neoplasias Colorrectales/diagnóstico por imagen , Proteínas de Unión al ADN , Fluorodesoxiglucosa F18/farmacocinética , Fusobacterium nucleatum , Microbioma Gastrointestinal , Regulación Neoplásica de la Expresión Génica , Histona Acetiltransferasas , Humanos , Ratones , Fosfopiruvato Hidratasa , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Radiofármacos/farmacocinética , Transducción de Señal , Células Tumorales Cultivadas , Proteínas Supresoras de TumorRESUMEN
BACKGROUND: To investigate the effect of intravenous injection of dexmedetomidine combined with parecoxib sodium on sedation and anxiety and stress response of tracheal intubation in patients undergoing functional endoscopic sinus surgery. METHODS: One hundred twenty patients undergoing endoscopic sinus surgery were randomly divided into four groups: group DP, group D, group P and group N. The blood pressure (BP), heart rate (HR), blood oxygen saturation (SPO2), EEG, bispectral index (BIS), Ramsay sedation score and state anxiety questionnaire (SAI) were recorded before administration (T0), 10 min (T1), 20 min (T2) and 30 min (T3) after administration. After 30 min, endotracheal intubation was performed after anesthesia induction. The BP, HR, SPO2 were recorded 1 min before intubation (T4), intubation (T5), 3 min (T6) after intubation, 5 min (T7) after intubation, and blood samples were collected from patients before administration and after intubation 2 min to detect serum cortisol (Cor), adrenalin (E) norepinephrine (NE) and blood glucose (BS). RESULTS: There was no significant difference in Ramsay sedation score before anesthesia, but the Ramsay sedation score in group DãDP was significantly higher than that in group P and group N, the BIS, BP, HR and anxiety scores were significantly lower than those in the group P and group N (p < 0.05). There was no significant difference in Ramsay sedation score, BIS value, anxiety score and BP, HR between group D and group DP (p > 0.05). Compared with T4, there was no significant difference in BIS and BP, HR in group D, group DP and group P (p > 0.05), but the BIS, BP and HR in group N were significantly higher than T4, (p < 0.05). Three minutes after intubation there was no statistical difference in the changes of Cor, E, NE and BS values compared with before intubation in group P and group DP (p > 0.05), but the changes of Cor, E, NE and BS values were significantly lower than that in group N (p < 0.05). Compared with T0, the values of NE, E, Cor, BS decreased in group D, DP and P at T4, group DP decreased more significantly than group D (p < 0.05). while the NE, E, Cor, BS of T6 are at the same level as the base value. In group N, the NE, E, Cor, BS of T4 were at the same level of T0, but significantly higher at T6.And at T6, NE and E in group D, P and N were significantly different from those in group DP (p < 0.05). CONCLUSION: Preoperative intravenous infusion of dexmedetomidine combined with parecoxib sodium by functional nasal endoscopy can not only calm and resist anxiety, but also better prevent stress response of endotracheal intubation, which is a safe and effective way of preoperative medication. TRIAL REGISTRATION: ChiCTR-OPN-17010444 . Prospectively registered on 16 January 2017.
Asunto(s)
Ansiedad/tratamiento farmacológico , Sedación Consciente , Dexmedetomidina/administración & dosificación , Intubación Intratraqueal , Isoxazoles/administración & dosificación , Senos Paranasales/cirugía , Estrés Psicológico/prevención & control , Adulto , Endoscopía , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Potential Cytochrome P450s (CYPs) 1A1 MspI, 1A1 Ile462Val, 1A2*1 F, and/or 1A2*1C polymorphisms have been implicated in gastric cancer risk among different ethnicities. We aimed to explore the effect of CYP 1A1 MspI, 1A1 Ile462Val, 1A2*1 F, and/or 1A2*1C polymorphisms on the susceptibility to gastric cancer among different ethnicities through a systematic review and meta-analysis. Each initially included article was scored for quality appraisal. Desirable data were extracted and registered into databases. A number of 11 studies were ultimately eligible for the meta-analysis of CYP1A1 MspI polymorphism, eight studies for the meta-analysis of 1A1 Ile462Val polymorphism, and two studies for the meta-analysis of 1A2*1 F polymorphism. None of genetic model was evidently suggested, and thus all the genetic models were presented. Potential sources of heterogeneity were sought out via subgroup and sensitivity analyses, and publication biases were estimated. In our meta-analysis, significant results could be found in mutational heterozygous CT genotype, compared with wild TT genotype, among large sample size subgroup for CYP1A1 MspI polymorphism. Regarding CYP1A1 Ile462Val polymorphism, no statistically significant results could be found. For CYP1A2*1 F polymorphism, mutational heterozygous AC genotype, compared with wild-type AA, has deleterious effects, whereas mutational homozygous CC genotype, compared with mutational heterozygous type AC, has protective effects but lacks statistically significant difference despite its a proximity to 0.05. Combined mutational homozygous CC genotype and wild-type homozygous AA, compared with mutational heterozygous AC genotype, has protective effects. Our meta-analysis suggests no associations between CYP1A1 Ile462Val polymorphism and gastric cancer, but possible associations between CYP1A1 MspI and CYP1A2*1 F polymorphisms and gastric cancer, which needs to be further reinforced or refuted among different ethnicities in well-designed large-scale high-quality studies.
Asunto(s)
Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Neoplasias Gástricas/genética , Genotipo , Humanos , Sesgo de Publicación , Riesgo , Neoplasias Gástricas/etnologíaRESUMEN
OBJECTIVE: The aim of this study was to investigate the relationship of MACC-1 (metastasis-associated in colon cancer 1) and microRNA (miRNA) hsa-miR-574-5p and the function of hsa-miR-574-5p in colorectal cancer liver metastasis. METHODS: Liver-metastatic nude mice model was constructed by injecting two human colorectal cancer cell lines (SW1116 and HCT116) labeled with green fluorescent protein (GFP) through spleen, and liver metastasis incidences were evaluated. We identified miRNAs that might regulate MACC-1 expression by bioinformatics analysis and further investigated the relationship of MACC-1 and hsa-miR-574-5p by luciferase reporter assay, quantitative RT-PCR and western blot. The effect of hsa-miR-574-5p on colony formation, cell invasion and cell spheroid formation was investigated by antisense transfected HCT116 cells and miRNA mimic transfected SW1116 cells. RESULTS: The volume of liver metastasis induced by SW1116 cells (25.0 ± 4.4%) was significantly higher than that induced by HCT116 cells. Bioinformatics analysis showed hsa-miR-574-5p negatively regulated MACC-1 and then their interaction was demonstrated at mRNA and protein level. The direct relation between them was confirmed by luciferase reporter assay. And the knockdown of has-miR-574-5p demonstrated increased colony formation, cell invasion and cell spheroid formation in HCT116 cells, compared to control group (P < 0.05). Reverse results were obtained in mimic transfected SW1116 cells. CONCLUSION: Our work firstly demonstrated that hsa-miR-574-5p negatively regulated MACC-1 expression in colorectal cancer cells. It was partly elucidated that hsa-miR-574-5p played a suppressive role in colorectal cancer liver metastasis by negatively directing MACC-1 expression, offering a novel therapeutic approach for colorectal cancer liver metastasis.
RESUMEN
OBJECTIVE: Branched-chain amino acid (BCAA) metabolism is involved in the development of colorectal cancer (CRC); however, the underlying mechanism remains unclear. Therefore, this study investigates the role of BCAA metabolism in CRC progression. METHODS: Dietary BCAA was administered to both azoxymethane-induced and azoxymethane/dextran sodium sulfate-induced CRC mouse models. The expression of genes related to BCAA metabolism was determined using RNA sequencing. Adjacent tissue samples, obtained from 58 patients with CRC, were subjected to quantitative real-time PCR and immunohistochemical analysis. Moreover, the suppressive role of branched-chain aminotransferase 2 (BCAT2) in cell proliferation, apoptosis, and xenograft mouse models was investigated. Alterations in BCAAs and activation of downstream pathways were also assessed using metabolic analysis and western blotting. RESULTS: High levels of dietary BCAA intake promoted CRC tumorigenesis in chemical-induced CRC and xenograft mouse models. Both the mRNA and protein levels of BCAT2 were decreased in tumor tissues of patients with CRC compared to those in normal tissues. Proliferation assays and xenograft models confirmed the suppressive role of BCAT2 in CRC progression. Furthermore, the accumulation of BCAAs caused by BCAT2 deficiency facilitated the chronic activation of mTORC1, thereby mediating the oncogenic effect of BCAAs. CONCLUSION: BCAT2 deficiency promotes CRC progression through inhibition of BCAAs metabolism and chronic activation of mTORC1.
Asunto(s)
Neoplasias Colorrectales , Proteínas Gestacionales , Humanos , Ratones , Animales , Aminoácidos de Cadena Ramificada/metabolismo , ARN Mensajero , Diana Mecanicista del Complejo 1 de la Rapamicina , Azoximetano , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/genética , Transaminasas/genética , Transaminasas/metabolismo , Proteínas Gestacionales/metabolismo , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/metabolismoRESUMEN
Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment.
RESUMEN
BACKGROUND: The efficacy of Vonoprazan-amoxicillin dual therapy (VAT) in the treatment of Helicobacter pylori (H. pylori) is controversial. AIM: To evaluate the efficacy of VAT in the Chinese population. METHODS: This prospective, multicenter, randomized, open-label, and two-stage study was conducted at 23 centers in Fujian, China (May 2021-April 2022). H. pylori-infected patients were randomized to bismuth quadruple therapy (BQT), BQT-Vonoprazan (BQT-V), seven-day VAT (VAT-7), ten-day VAT (VAT-10), and fourteen-day VAT (VAT-14) groups. The primary endpoint was the H. pylori eradication rate. The secondary endpoint was the frequency of adverse events. This study was registered with the Chinese Clinical Trial Registry, ChiCTR2100045778. RESULTS: In the first stage, VAT-7 and BQT-V groups were selected for early termination because less than 23 among 28 cases were eradicated. In the second stage, the eradication rates for BQT, VAT-10, and VA-14 were 80.2% [95% confidence interval (95%CI): 71.4%-86.8%], 93.2% (86.6%-96.7%), 92.2% (85.3%-96.0%) in the intention-to-treat (ITT) analysis, and 80.9% (95%CI: 71.7%-87.5%), 94.0% (87.5%-97.2%), and 93.9% (87.4%-97.2%) in the per-protocol analysis. The ITT analysis showed a higher eradication rate in the VAT-10 and VAT-14 groups than in the BQT group (P = 0.022 and P = 0.046, respectively). The incidence of adverse events in the VAT-10 and VAT-14 groups was lower than in the BQT group (25.27% and 13.73% vs 37.62%, respectively; P < 0.001). CONCLUSION: VAT with a duration of 10 or 14 days achieves a higher eradication rate than the BQT, with a more tolerable safety profile in H. pylori-infected patients in Fujian.
Asunto(s)
Amoxicilina , Antibacterianos , Quimioterapia Combinada , Infecciones por Helicobacter , Helicobacter pylori , Inhibidores de la Bomba de Protones , Pirroles , Sulfonamidas , Humanos , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/diagnóstico , Persona de Mediana Edad , Masculino , Sulfonamidas/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Helicobacter pylori/efectos de los fármacos , Helicobacter pylori/aislamiento & purificación , Femenino , Estudios Prospectivos , Amoxicilina/administración & dosificación , Amoxicilina/efectos adversos , Amoxicilina/uso terapéutico , China/epidemiología , Quimioterapia Combinada/métodos , Pirroles/uso terapéutico , Pirroles/efectos adversos , Pirroles/administración & dosificación , Resultado del Tratamiento , Adulto , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/efectos adversos , Antibacterianos/efectos adversos , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Anciano , Pueblos del Este de AsiaRESUMEN
Periphytic algae are important primary producers in water bodies, which play an important role in maintaining ecological function and water purification. Previous studies have shown that plastic is a good substrate for periphytic algae, and different plastic materials have different effects on the colonization of periphytic algae; however, there are few reports on the effects of plastic color on the growth of periphytic algae. In this study, polycarbonate plastic (PC) of various colors were used as the substrate to study the effects of different colors on the growth and community structure of periphytic algae by measuring the biomass, photosynthetic activity, and community composition. The results showed that the growth of periphytic algae was inhibited by the brown PC plastic, and the contents of chlorophyll a and dry weight in this group were significantly lower than those in other groups. Green PC plastic inhibited the photosynthetic activity of periphytic algae, and the actual photosynthetic efficiency (Yield) of the group was significantly lower than that of the other groups. The influence of PC plastic with different colors on periphytic algae occurred mainly in the early colonization/development stage but was not significant in the late community maturity stage. On day seven of the experiment, the community composition of periphytic algae was significantly different between the transparent PC plastic group and the green PC plastic group. By contrast, on days 25 and 40, there were no significant differences in the community structure of periphytic algae. In the early stage of the experiment, the dominant genus was Pseudoranea (Cyanophyta), and in the middle and mature stages, the dominant genus was Mougeotia (Chlorophyta). In this study, the effects of different colors of polycarbonate plastics on periphytic algae were investigated, which provided new insights for selecting suitable substrates for water pollution treatment by using periphyton biotechnology.
Asunto(s)
Fotosíntesis , Plásticos , Clorofila A , BiomasaRESUMEN
Maladaptation of host-microbiota metabolic interplay plays a critical role in colorectal cancer initiation. Here, through a combination of single-cell transcriptomics, microbiome profiling, metabonomics, and clinical analysis on colorectal adenoma and carcinoma tissues, we demonstrate that host's urea cycle metabolism is significantly activated during colorectal tumorigenesis, accompanied by the absence of beneficial bacteria with ureolytic capacity, such as Bifidobacterium, and the overabundance of pathogenic bacteria lacking ureolytic function. Urea could enter into macrophages, inhibit the binding efficiency of p-STAT1 to SAT1 promotor region, and further skew macrophages toward a pro-tumoral phenotype characterized by the accumulation of polyamines. Treating a murine model using urea cycle inhibitors or Bifidobacterium-based supplements could mitigate urea-mediated tumorigenesis. Collectively, this study highlights the utility of urea cycle inhibitors or therapeutically manipulating microbial composition using probiotics to prevent colorectal cancer.
Asunto(s)
Neoplasias Colorrectales , Microbioma Gastrointestinal , Microbiota , Ratones , Animales , Microbioma Gastrointestinal/fisiología , Carcinogénesis , Neoplasias Colorrectales/patología , Transformación Celular NeoplásicaRESUMEN
Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.
Asunto(s)
Neoplasias Colorrectales , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Limosilactobacillus reuteri , Microbiota , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Triptófano , Estudios Retrospectivos , Neoplasias Colorrectales/prevención & controlRESUMEN
Immune checkpoint blockade therapy with anti-PD-1 monoclonal antibody (mAb) is a treatment for colorectal cancer (CRC). However, some patients remain unresponsive to PD-1 blockade. The gut microbiota has been linked to immunotherapy resistance through unclear mechanisms. We found that patients with metastatic CRC who fail to respond to immunotherapy had a greater abundance of Fusobacterium nucleatum and increased succinic acid. Fecal microbiota transfer from responders with low F. nucleatum, but not F. nucleatum-high non-responders, conferred sensitivity to anti-PD-1 mAb in mice. Mechanistically, F. nucleatum-derived succinic acid suppressed the cGAS-interferon-ß pathway, consequently dampening the antitumor response by limiting CD8+ T cell trafficking to the tumor microenvironment (TME) in vivo. Treatment with the antibiotic metronidazole reduced intestinal F. nucleatum abundance, thereby decreasing serum succinic acid levels and resensitizing tumors to immunotherapy in vivo. These findings indicate that F. nucleatum and succinic acid induce tumor resistance to immunotherapy, offering insights into microbiota-metabolite-immune crosstalk in CRC.
Asunto(s)
Neoplasias Colorrectales , Infecciones por Fusobacterium , Animales , Ratones , Fusobacterium nucleatum , Neoplasias Colorrectales/tratamiento farmacológico , Ácido Succínico , Infecciones por Fusobacterium/microbiología , Inmunoterapia , Microambiente TumoralRESUMEN
BACKGROUND: A key factor underlying the control of the cellular growth, size and proliferation involves the regulation of the total protein synthesis. Most often, the initial stages of mRNA translation are rate limiting, which involves a group of eukaryotic translation initiation factors (EIFs). Research advances focused on the inhibition of their expression and activity hold the key to the initiation and progression of tumor and tumor prognosis. METHOD: We performed RNA interference (RNAi) with the lentivirus vector system to silence the EIF3B gene using the colon cancer cell strain SW1116. The negative control included the normal target cells infected with the negative control virus whereas the knockdown cells included the normal target cells transfected with the RNAi target virus. We tested the inhibition resulting from the decreased expression of EIF3B gene on the proliferation rate of SW1116 cells, including the cell cycle, apoptosis and clonability. RESULTS: Compared with the negative control, the impact of EIF3B gene expression in SW1116 cells on the levels of mRNA and protein in the knockdown group, was significantly inhibited (P < 0.01). Furthermore, the cell proliferation rate and clonability were also significantly inhibited (P < 0.01). The apoptosis rate increased significantly (P < 0.05). A significant decrease in the number of cells in the G1 phase (P < 0.01) and significant increases in S (P < 0.01) and G2 phases (P < 0.05) were observed. CONCLUSIONS: The silencing of EIF3B gene expression inhibits the proliferation of colon cancer cells.
Asunto(s)
Apoptosis , Proliferación Celular , Neoplasias del Colon/patología , Factor 3 de Iniciación Eucariótica/genética , Interferencia de ARN , ARN Interferente Pequeño/genética , Western Blotting , Ciclo Celular , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Factor 3 de Iniciación Eucariótica/metabolismo , Vectores Genéticos , Humanos , Lentivirus/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales CultivadasRESUMEN
P. (T.) anningense sp. n. and P. (T.) biloborum sp. n. are described and illustrated as male imagines from Oriental China. DNA barcodes of two new species are also presented. A key to known male imagines of the subgenus Tripodura from China is given.
Asunto(s)
Chironomidae , Dípteros , Distribución Animal , Animales , China , Chironomidae/genética , Ciudades , MasculinoRESUMEN
Tumor cells evade T cell-mediated immunosurveillance via the interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells. Strategies disrupting PD-1/PD-L1 have shown clinical benefits in various cancers. However, the limited response rate prompts us to investigate the molecular regulation of PD-L1. Here, we identify trafficking protein particle complex subunit 4 (TRAPPC4), a major player in vesicular trafficking, as a crucial PD-L1 regulator. TRAPPC4 interacts with PD-L1 in recycling endosomes, acting as a scaffold between PD-L1 and RAB11, and promoting RAB11-mediated recycling of PD-L1, thus replenishing its distribution on the tumor cell surface. TRAPPC4 depletion leads to a significant reduction of PD-L1 expression in vivo and in vitro. This reduction in PD-L1 facilitates T cell-mediated cytotoxicity. Overexpression of Trappc4 sensitizes tumor cells to checkpoint therapy in murine tumor models, suggesting TRAPPC4 as a therapeutic target to enhance anti-tumor immunity.
Asunto(s)
Antígeno B7-H1/inmunología , Neoplasias Colorrectales/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Proteínas del Tejido Nervioso/inmunología , Proteínas de Transporte Vesicular/inmunología , Animales , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Citotoxicidad Inmunológica/genética , Citotoxicidad Inmunológica/inmunología , Endosomas/inmunología , Endosomas/metabolismo , Células HCT116 , Humanos , Espacio Intracelular/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Unión Proteica , Transporte de Proteínas , Interferencia de ARN , Linfocitos T/inmunología , Linfocitos T/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMEN
Aiming to identify rare high-penetrance mutations in new genes for the underlying predisposition in familial colorectal cancer (CRC), we performed whole-exome sequencing in 24 familial CRCs. Mutations in genes that regulate DNA repair (RMI1, PALB2, FANCI) were identified that were related to the Fanconi anemia DNA repair pathway. In one pedigree, we found a nonsense mutation in CHEK2. CHEK2 played an essential role in cell cycle and DNA damage repair. Somatic mutation analysis in CHEK2 variant carriers showed mutations in TP53, APC, and FBXW7. Loss of heterozygosity was found in carcinoma of CHEK2 variant carrier, and IHC showed loss of Chk2 expression in cancer tissue. We identified a second variant in CHEK2 in 126 sporadic CRCs. A KO cellular model for CHEK2 (CHEK2KO) was generated by CRISPR/Cas9. Functional experiments demonstrated that CHEK2KO cells showed defective cell cycle arrest and apoptosis, as well as reduced p53 phosphorylation, upon DNA damage. We associated germline mutations in genes that regulate the DNA repair pathway with the development of CRC. We identified CHEK2 as a regulator of DNA damage response and perhaps as a gene involved in CRC germline predisposition. These findings link CRC predisposition to the DNA repair pathway, supporting the connection between genome integrity and cancer risk.
Asunto(s)
Quinasa de Punto de Control 2/genética , Neoplasias Colorrectales/genética , Reparación del ADN/genética , Predisposición Genética a la Enfermedad/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Quinasa de Punto de Control 2/metabolismo , Neoplasias Colorrectales/metabolismo , Daño del ADN , Proteínas de Unión al ADN/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Femenino , Técnicas de Inactivación de Genes , Mutación de Línea Germinal , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Linaje , Fosforilación/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Secuenciación del Exoma , Adulto JovenRESUMEN
Long non-coding RNAs (lncRNAs) play key roles in colorectal carcinogenesis. Here, we aimed to identify the risk SNP-induced lncRNAs and to investigate their roles in colorectal carcinogenesis. First, we identified rs6695584 as the causative SNP in 1q41 locus. The A>G mutation of rs6695584 created a protein-binding motif of BATF, altered the enhancer activity, and subsequently activated lncSLCC1 expression. Further validation in two independent CRC cohorts confirmed the upregulation of lncSLCC1 in CRC tissues, and revealed that increased lncSLCC1 expression was associated with poor survival in CRC patients. Mechanistically, lncRNA-SLCC1 interacted with AHR and transcriptionally activated HK2 expression, the crucial enzyme in glucose metabolism, thereby driving the glycolysis pathway and accelerating CRC tumor growth. The functional assays revealed that lncSLCC1 induced glycolysis activation and tumor growth in CRC mediated by HK2. In addition, HK2 was upregulated in colorectal cancer tissues and positively correlated with lncSLCC1 expression and patient survival. Taken together, our findings reveal a risk SNP-mediated oncogene lncRNA-SLCC1 promotes CRC through activating the glycolysis pathway.
Asunto(s)
Carcinogénesis/genética , Neoplasias Colorrectales/genética , Hexoquinasa/genética , ARN Largo no Codificante/genética , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Glucólisis/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Transducción de Señal/genéticaRESUMEN
The larva and female of Polypedilum (Probolum) bullum Zhang Wang associated with morphological characteristics and DNA barcodes are described and illustrated for the first time. The female is characteristic with developed dorsomesal lobe and ventrolateral lobe both densely covered with apical setae, ventrolateral lobe partially covered by dorsomesal lobe. The larva is distinguished by the shape of mentum, pecten epipharyngis, labral SI and labral SII.
Asunto(s)
Chironomidae , Código de Barras del ADN Taxonómico , Animales , Femenino , LarvaRESUMEN
Genome-wide association studies (GWASs) implicate 16q22.1 locus in risk for colorectal cancer (CRC). However, the underlying oncogenic mechanisms remain unknown. Here, through comprehensive filtration, we prioritized rs7198799, a common SNP in the second intron of the CDH1, as the putative causal variant. In addition, we found an association of CRC-risk allele C of rs7198799 with elevated transcript level of biological plausible candidate gene ZFP90 via expression quantitative trait loci analysis. Mechanistically, causal variant rs7198799 resides in an enhancer element and remotely regulate ZFP90 expression by targeting the transcription factor NFATC2. Remarkably, CRISPR/Cas9-guided single-nucleotide editing demonstrated the direct effect of rs7198799 on ZFP90 expression and CRC cellular malignant phenotype. Furthermore, ZFP90 affects several oncogenic pathways, including BMP4, and promotes carcinogenesis in patients and in animal models with ZFP90 specific genetic manipulation. Taken together, these findings reveal a risk SNP-mediated long-range regulation on the NFATC2-ZFP90-BMP4 pathway underlying the initiation of CRC.