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BACKGROUND: Enterococcus faecalis (Efa) has been shown to be a "driver bacteria" in the occurrence and development of colorectal cancer (CRC). This study aims to explore the effect of specific metabolites of Efa on CRC. METHODS: The pro-tumor effects of Efa were assessed in colonic epithelial cells. The tumor-stimulating molecule produced by Efa was identified using liquid chromatography mass spectrometry (LC-MS). The proliferative effect of metabolites on CRC cells in vitro was assayed as well. The concentration of vascular endothelial growth factor A (VEGFA) and interleukin-8 (IL-8) was determined using enzyme-linked immunosorbent assay (ELISA). Tubular formation assay of human umbilical vein endothelial cells (HUVEC) and cell migration assay were applied to study angiogenesis. Additionally, western blot analysis was used to investigate key regulatory proteins involved in the angiogenesis pathway. Tumor growth was assessed using mouse models with two CRC cells and human colon cancer organoid. RESULTS: Co-incubation with the conditioned medium of Efa increased the proliferation of cultured CRC cells. Biliverdin (BV) was determined as the key metabolite produced by Efa using LC-MS screening. BV promoted colony formation and cell proliferation and inhibited cell cycle arrest of cultured CRC cells. BV significantly increased the expression level of IL-8 and VEGFA by regulating the PI3K/AKT/mTOR signaling pathway, leading to the acceleration of angiogenesis in CRC. The up-regulation of proliferation and angiogenesis by BV were also confirmed in mice. CONCLUSION: In conclusion, BV, as the tumor-stimulating metabolite of Efa, generates proliferative and angiogenic effects on CRC, which is mainly mediated by the activation of PI3K/AKT/mTOR.
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Neoplasias Colorretais , Fator A de Crescimento do Endotélio Vascular , Humanos , Animais , Camundongos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias Colorretais/patologia , Interleucina-8 , Enterococcus faecalis/metabolismo , Biliverdina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neovascularização Patológica/patologia , Serina-Treonina Quinases TOR/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proliferação de CélulasRESUMO
BACKGROUND: Primary gastric linitis plastica (GLP) is a distinct phenotype of gastric cancer with poor survival. Comprehensive molecular profiles and putative therapeutic targets of GLP remain undetermined. METHODS: We subjected 10 tumor-normal tissue pairs to whole exome sequencing (WES) and whole transcriptome sequencing (WTS). 10 tumor samples were all GLP which involves 100% of the gastric wall macroscopically. TCGA data were compared to generate the top mutated genes and the overexpressed genes in GLP. RESULTS: Our results reveal that GLP has distinctive genomic and transcriptomic features, dysfunction in the Hippo pathway is likely to be a key step during GLP development. 6 genes were identified as significantly highly mutated genes in GLP, including AOX1, ANKRD36C, CPXM1, PTPN14, RPAP1, and DCDC1). MUC6, as a previously identified gastric cancer driver gene, has a high mutation rate (20%) in GLP. 20% of patients in our GLP cohort had CDH1 mutations, while none had RHOA mutations. GLP exhibits high immunodeficiency and low AMPK pathway activity. Our WTS results showed that 3 PI3K-AKT pathway-related genes (PIK3R2, AKT3, and IGF1) were significantly up-regulated in GLP. Two genes were identified using immunohistochemistry (IHC), IGF2BP3 and MUC16, which specifically expressed in diffuse-type-related gastric cancer cell lines, and its knockdown inhibits PI3K-AKT pathway activity. CONCLUSIONS: We provide the first integrative genomic and transcriptomic profiles of GLP, which may facilitate its diagnosis, prognosis, and treatment.
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Linite Plástica , Neoplasias Gástricas , Humanos , Linite Plástica/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Transcriptoma , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Mutação , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteínas de Transporte/genéticaRESUMO
It is widely acknowledged that gastric cancer seriously affects the quality of life and survival of patients. The correlation between the microbiota and gastric cancer has attracted extensive attention in recent years, nonetheless the specific mechanism of its impact on gastric cancer remain largely unclear. Recent studies have shown that in addition to its role in the host's inflammatory and immune response, the microbiota can also affect the occurrence and development of gastric cancer by affecting the expression of miRNAs. This paper brings together all currently available data on miRNAs, microbiota and gastric cancer, and preliminarily describes the relationship among them.
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MicroRNAs , Microbiota , Neoplasias Gástricas , Interações entre Hospedeiro e Microrganismos , Humanos , MicroRNAs/genética , Qualidade de Vida , Neoplasias Gástricas/genéticaRESUMO
BACKGROUND: Globally, gastric cancer is the third most common cancer and the third leading cause of cancer death. Proximal and distal gastric cancers have distinct clinical and biological behaviors. The microbial composition and metabolic differences in proximal and distal gastric cancers have not been fully studied and discussed. METHODS: In this study, the gastric microbiome of 13 proximal gastric cancer tissues, 16 distal gastric cancer tissues, and their matched non-tumor tissues were characterized using 16S rRNA amplicon sequencing. Additionally, 10 proximal gastric cancer tissues, 11 distal gastric cancer tissues, and their matched non-tumor tissues were assessed by untargeted metabolomics. RESULTS: There was no significant difference in microbial diversity and richness between the proximal and distal gastric cancer tissues. At the genus level, the abundance of Rikenellaceae_RC9_gut_group, Porphyromonas, Catonella, Proteus, Oribacterium, and Moraxella were significantly increased in Proximal T, whereas that of Methylobacterium_Methylorubrum was significantly increased in Distal T. The untargeted metabolomics analysis revealed 30 discriminative metabolites between Distal T and Distal N. In contrast, there were only 4 discriminative metabolites between Proximal T and Proximal N. In distal gastric cancer, different metabolites were scattered through multiple pathway, including the sphingolipid signaling pathway, arginine biosynthesis, protein digestion and absorption, alanine, aspartate and, glutamate metabolism, etc.In proximal gastric cancer, differential microbial metabolites were mainly related to hormone metabolism. CONCLUSION: Methylobacterium-Methylorubrum was significantly increased in Distal T, positively correlated with cancer-promoting metabolites, and negatively correlated with cancer-inhibiting metabolites. Rikenellaceae_RC_gut_group was significantly increased in Proximal T and positively correlated with cancer-promoting metabolites. Further studies regarding the functions of the above-mentioned microorganisms and metabolites were warranted as the results may reveal the different mechanisms underlying the occurrence and development of proximal and distal gastric cancers and provide a basis for future treatments. IMPORTANCE: First, the differences in microbial composition and metabolites between the proximal and distal gastric cancers were described; then, the correlation between microbiota and metabolites was preliminarily discussed. These microbes and metabolites deserve further investigations as they may reveal the different mechanisms involved in the occurrence and development of proximal and distal gastric cancers and provide a basis for future treatments.
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Microbiota , Neoplasias Gástricas , Alanina , Arginina , Ácido Aspártico , Fezes/microbiologia , Glutamatos , Hormônios , Humanos , Metabolômica/métodos , RNA Ribossômico 16S/genética , EsfingolipídeosRESUMO
Six-junction GaAs laser power converts (LPCs) were designed and fabricated. Each subcell is vertically connected by p++-AlGaAs: C/n++-AlGaAs: Si: Te (1:2) tunnel junction with good thermal stability and a record peak tunneling current density of 1867 A/cm2. The I-V characteristics of LPCs with an aperture of 10×10 mm2 were investigated as a function of laser power and temperature. Maximum conversion efficiency and output power of 57.7% and 15.4 W, respectively, and a continuous stable operation at 22.9 W for over 550 hours were demonstrated. The temperature coefficient of conversion efficiency and open-circuit voltage were -0.197%abs/°C and -8.15 mV/°C, respectively, under 808 nm laser illumination of 21.0 W. Furthermore, an array of 100 large-scale (41×46 mm2) LPCs with an output power of 179 W under 1 kW laser irradiation at 20 m wireless transmission was developed.
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InGaAs metamorphic laser power converters (LPCs) have the potential to deliver electrical energy over distances of several kilometers. In this study, metalorganic chemical vapor deposition (MOCVD) was used to grow InGaAs-based LPCs with an absorption wavelength of 1064â nm. At step thicknesses of 2800â nm, overshoot thicknesses of 6000â nm, reverse component and thicknesses of 2.4% and 700â nm, respectively, a surface roughness of 6.0â nm and InGaAs (24%) lattice relaxation of 93.7% of the InGaAs metamorphic buffer were obtained. The I-V characteristics of LPCs with 10 × 10 mm2 apertures were investigated as a function of laser power and temperature. The maximum conversion efficiency of 44.1% and 550 hours of continuous stable operation at 4 W were demonstrated. Under 1064â nm laser illumination of 4 W, the temperature coefficients for the conversion efficiency and open-circuit voltage were -0.1%abs/°C and -1.6â mV/°C, respectively, and the LPC output power fluctuation was less than 0.5% during 216 hours of continuous temperature change from 20 to 100°C.
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BACKGROUND: Gastric cancer (GC) is one of the leading causes of cancer deaths with high heterogeneity. There is currently a paucity of clinically applicable molecular classification system to guide precise medicine. METHODS: A total of 70 Chinese patients with GC were included in this study and whole-exome sequencing was performed. Unsupervised clustering was undertaken to identify genomic subgroups, based on mutational signature, copy number variation, neoantigen, clonality, and essential genomic alterations. Subgroups were characterized by clinicopathological factors, molecular features, and prognosis. RESULTS: We identified 32 significantly mutated genes (SMGs), including TP53, ARID1A, PIK3CA, CDH1, and RHOA. Of these, PREX2, PIEZO1, and FSIP2 have not been previously reported in GC. Using a novel genome-based classification method that integrated multidimensional genomic features, we categorized GC into four subtypes with distinct clinical phenotypes and prognosis. Subtype 1, which was predominantly Lauren intestinal type, harbored recurrent TP53 mutation and ERBB2 amplification, high tumor mutation burden (TMB)/tumor neoantigen burden (TNB), and intratumoral heterogeneity, with a liver metastasis tendency. Subtype 2 tended to occur at an elder age, accompanying with frequent TP53 and SYNE1 mutations, high TMB/TNB, and was associated with poor prognosis. Subtype 3 and subtype 4 included patients with mainly diffuse/mixed type tumors, high frequency of peritoneal metastasis, and genomical stability, whereas subtype 4 was associated with a favorable prognosis. CONCLUSIONS: By integrating multidimensional genomic characteristics, we proposed a novel genomic classification system of GC associated with clinical phenotypes and provided a new insight to facilitate genome-guided risk stratification and disease management.
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Predisposição Genética para Doença , Genômica , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , China , Estudos de Coortes , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Medicina de PrecisãoRESUMO
Adenosylmethionine decarboxylase 1 (AMD1) is a key enzyme involved in biosynthesis of polyamines including spermidine and spermine. The potential function of AMD1 in human gastric cancers is unknown. We analyzed AMD1 expression level in 319 human gastric cancer samples together with the adjacent normal tissues. The protein expression level of AMD1 was significantly increased in human gastric cancer samples compared with their corresponding para-cancerous histological normal tissues (P < 0.0001). The expression level of AMD1 was positively associated with Helicobactor pylori 16sRNA (P < 0.0001), tumor size (P < 0.0001), tumor differentiation (P < 0.05), tumor venous invasion (P < 0.0001), tumor lymphatic invasion (P < 0.0001), blood vessel invasion (P < 0.0001), and tumor lymph node metastasis (TNM) stage (P < 0.0001). Patients with high expression of AMD1 had a much shorter overall survival than those with normal/low expression of AMD1. Knockdown of AMD1 in human gastric cancer cells suppressed cell proliferation, colony formation and cell migration. In a tumor xenograft model, knockdown of AMD1 suppressed the tumor growth in vivo. Inhibition of AMD1 by an inhibitor SAM486A in human gastric cancer cells arrested cell cycle progression during G1-to-S transition. Collectively, our studies at the cellular, animal and human levels indicate that AMD1 has a tumorigenic effect on human gastric cancers and affect the prognosis of the patients.
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Adenocarcinoma/patologia , Adenosilmetionina Descarboxilase/metabolismo , Carcinogênese/patologia , Infecções por Helicobacter/patologia , Neoplasias Gástricas/patologia , Adenocarcinoma/microbiologia , Adenocarcinoma/mortalidade , Adenosilmetionina Descarboxilase/antagonistas & inibidores , Adenosilmetionina Descarboxilase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Amidinas/farmacologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Infecções por Helicobacter/microbiologia , Helicobacter pylori/genética , Helicobacter pylori/isolamento & purificação , Humanos , Indanos/farmacologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Poliaminas/metabolismo , Prognóstico , Estômago/patologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/mortalidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ovarian metastasis is one of the major causes of treatment failure in patients with gastric cancer (GC). However, the genomic characteristics of ovarian metastasis in GC remain poorly understood. In this study, we enroll 74 GC patients with ovarian metastasis, with 64 having matched primary and metastatic samples. Here, we show a characterization of the mutation landscape of this disease, alongside an investigation into the molecular heterogeneity and pathway mutation enrichments between synchronous and metachronous metastasis. We classify patients into distinct clonal evolution patterns based on the distribution of mutations in paired samples. Notably, the parallel evolution group exhibits the most favorable prognosis. Additionally, by analyzing the differential response to chemotherapy, we identify potential biomarkers, including SALL4, CCDC105, and CLDN18, for predicting the efficacy of paclitaxel treatment. Furthermore, we validate that CLDN18 fusion mutations improve tumor response to paclitaxel treatment in GC with ovarian metastasis in vitro and vivo.
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Biomarcadores Tumorais , Mutação , Neoplasias Ovarianas , Paclitaxel , Neoplasias Gástricas , Paclitaxel/uso terapêutico , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Biomarcadores Tumorais/genética , Claudinas/genética , Claudinas/metabolismo , Evolução Molecular , Animais , Pessoa de Meia-Idade , Prognóstico , Linhagem Celular Tumoral , Camundongos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Idoso , Antineoplásicos Fitogênicos/uso terapêuticoRESUMO
BACKGROUND: Ovarian metastasis from gastric cancer (GC) is characterized by aggressive biological behavior and poor outcome. Currently, there is no standard treatment mode for such patients. Thus, we evaluated the efficacy of conversion therapy in patients with synchronous ovarian metastasis from GC in this study. METHODS: About 219 GC patients with ovarian metastasis in 2011-2020 were enrolled. Two groups were established based on the different treatment: the conversion therapy group (chemotherapy combined with surgical resection, CS group) and the non-conversion therapy group (NCS group). Propensity score matching (PSM) was used to analyze the efficacy of different treatment modes on the prognosis of these patients. RESULTS: Ninety-two patients were included according to PSM results, with 46 patients each in CS and NCS groups. The median overall survival (OS) in the CS group was notably better than that in the NCS group (p < 0.001). Twenty-six patients (56.52%) in the CS group achieved R0 resection, and they had a better prognosis (p = 0.003). Compared with patients who underwent simultaneous gastrectomy and ovarian metastasectomy (CSb group), those who underwent ovarian metastasectomy before systemic chemotherapy (CSa group) had a higher R0 resection rate (p = 0.016) and longer survival time (p = 0.002). A total of 38 patients (41.30%) across both groups received hyperthermic intraperitoneal chemotherapy (HIPEC), and these patients had a better survival (p = 0.043). CONCLUSION: The conversion therapy is safe and effective for patients with synchronous ovarian metastasis from GC and can improve their prognosis. However, our results need to be confirmed by more randomized controlled clinical studies.
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Neoplasias Ovarianas , Neoplasias Gástricas , Humanos , Feminino , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Pontuação de Propensão , Prognóstico , Quimioterapia Intraperitoneal Hipertérmica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Estudos Retrospectivos , Terapia Combinada , Taxa de SobrevidaRESUMO
The majority of patients with human epidermal growth factor receptor 2 (Her2)-positive gastric cancer develop refractory to Her2-targeted therapy, where upregulation of immune checkpoints plays an essential role. Herein, a recombinant fully human IgG1 bispecific antibody IBI315 targeting both PD-1 and Her2 is developed and its antitumor efficacy as well as the underlying mechanism is investigated. IBI315 crosslinks the physical interaction between Her2-positive tumor cells and PD-1-positive T cells, resulting in significantly enhanced antitumor effects compared to each parent antibody or their combination, both in vitro and in vivo mouse tumor models reconstituted with human immune cells using patient-derived xenografts and organoids. Moreover, IBI315 treatment also induces the recruitment and activation of immune cells in tumors. Mechanistically, IBI315 triggers gasdermin B (GSDMB)-mediated pyroptosis in tumor cells, leading to the activation and recruiments of T cells. The activated T cells secret IFNγ, enhancing GSDMB expression and establishing a positive feedback loop of T cell activation and tumor cell killing. Notably, GSDMB is found to be elevated in Her2-positive gastric cancer cells, providing a rationale for IBI315's efficacy. IBI315 is supported here as a promising bispecific antibody-based immunotherapy approach for Her2-positive gastric cancer in preclinical studies, broadening the therapeutic landscape of this patient population.
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Anticorpos Biespecíficos , Antineoplásicos , Neoplasias Gástricas , Humanos , Camundongos , Animais , Neoplasias Gástricas/tratamento farmacológico , Gasderminas , Piroptose , Receptor de Morte Celular Programada 1 , Linhagem Celular Tumoral , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêuticoRESUMO
BACKGROUND: Esophageal cancer (EC) is one of the most common human malignant tumors worldwide. Chromobox (CBX) family proteins are significant components of epigenetic regulatory complexes. It is reported that CBXs play critical roles in the oncogenesis and development of various tumors. Nonetheless, their functions and specific roles in EC remain vague and obscure. METHODS AND MATERIALS: We used multiple bioinformatics tools, including Oncomine, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), UALCAN, Kaplan-Meier plotter, cBioPortal, Metascape, TIMER2 and TISIDB, to investigate the expression profile, gene alterations and prognostic roles of CBX family proteins, as well as their association with clinicopathologic parameters, immune cells and immune regulators. In addition, RT-qPCR, Western blot, CCK8, colony formation, wound healing and transwell assays were performed to investigate the biological functions of CBX3 in EC cells. RESULTS: CBX3 and CBX5 were overexpressed in EC compared to normal tissues. Survival analysis revealed that high expression of CBX1 predicted worse disease-free survival (DFS) in EC patients. Functionally, CBXs might participate in mismatch repair, spliceosome, cell cycle, the Fanconi anemia pathway, tight junction, the mRNA surveillance pathway and the Hippo signaling pathway in EC development. Furthermore, CBXs were related to distinct immune cells infiltration and immune regulators. Additionally, depletion of CBX3 inhibited the proliferation, migration and invasion abilities of EC cells. CONCLUSIONS: Our study comprehensively investigated the expression pattern, prognostic value, and gene alterations of CBXs in EC, as well as their relationships with clinicopathologic variables, immune cells infiltration and immune regulators. These results suggested that CBX family proteins, especially CBX3, might be potential biomarkers in the progression of EC.
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Neoplasias Esofágicas , Transformação Celular Neoplásica , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Neoplasias Esofágicas/genética , Perfilação da Expressão Gênica , Humanos , Prognóstico , RNA Mensageiro/genéticaRESUMO
Gastric cancer (GC) is one of the main causes of cancer incidence rate and mortality worldwide. As the main breakthrough direction, the application of immune checkpoint inhibitors makes patients with GC have better prognosis, where PD-L1/PD-1 inhibitors in immunotherapy have good anti-tumor immune efficacy. Further understanding of the regulatory mechanism of PD-L1 in GC may bring substantial progress to the immunotherapy. In this review, we provide information on the endogenous and exogenous regulatory mechanisms of PD-L1 and its biological functions combined with current clinical trials of PD-L1/PD-1 inhibitors in GC. The malignant biological phenotypes caused by PD-L1 and the corresponding clinical combined treatment scheme have been reported. Identifying the biomarkers of the potential efficacy of immunotherapy and specifying the clinical immunotherapy scheme in combination with molecular characteristics of patients may maximize clinical benefits and better prognosis.
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Antígeno B7-H1 , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Terapia CombinadaRESUMO
Genomic features, including tumor mutation burden (TMB), microsatellite instability (MSI), and somatic copy number alteration (SCNA), had been demonstrated to be involved with the tumor microenvironment (TME) and outcome of gastric cancer (GC). We obtained profiles of TMB, MSI, and SCNA by processing 405 GC data from The Cancer Genome Atlas (TCGA) and then conducted a comprehensive analysis though "iClusterPlus." A total of two subgroups were generated, with distinguished prognosis, somatic mutation burden, copy number changes, and immune landscape. We revealed that Cluster1 was marked by a better prognosis, accompanied by higher TMB, MSIsensor score, TMEscore, and lower SCNA burden. Based on these clusters, we screened 196 differentially expressed genes (DEGs), which were subsequently projected into univariate Cox survival analysis. We constructed a 9-gene immune risk score (IRS) model using LASSO-penalized logistic regression. Moreover, the prognostic prediction of IRS was verified by receiver operating characteristic (ROC) curve analysis and nomogram plot. Another independent Gene Expression Omnibus (GEO) contained specimens from 109 GC patients was designed as an external validation. Our works suggested that the 9-gene-signature prediction model, which was derived from TMB, MSI, and SCNA, was a promising predictive tool for clinical outcomes in GC patients. This novel methodology may help clinicians uncover the underlying mechanisms and guide future treatment strategies.
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Purpose: Exosome component 5 (EXOSC5) is a non-catalytic component of the RNA exosome complex, which is interacted with the Zinc-finger antiviral protein to degrade the target RNA and aberrantly expressed in various malignances. We explored the molecular mechanisms and biological roles by which EXOSC5 promotes the progression of GC. Methods: We used quantitative real-time PCR, Western blotting and immunohistochemistry to analyze EXOSC5 expression in GC samples. An GC organoid-based functional model was assessed, and cancer cell CCK-8 assay, colony formation assay and flow cytometry were performed to reveal the role of EXOSC5 in GC cell proliferation and tumorigenesis. In vivo, nude mice tumorigenesis assay were performed to explore the effects of EXOSC5 knockdown on growth of GC. The roles of EXOSC5 on AKT and STAT3 signaling pathways were measured by Western blot. Results: The expression of EXOSC5 was up-regulated in GC tissues and cell lines compared with normal group, and highly expressed EXOSC5 indicated a poorer clinical outcome for GC patients and was positively correlated with tumor size and TNM stage. EXOSC5 overexpression facilitated the growth of GC cells and organoids, while EXOSC5 downregulation inhibited proliferation and induced G1/S phase transition arrest. Moreover, mechanistic studies demonstrated that EXOSC5 increased cyclinD1 expression levels and decreasing the expression levels of p21 and p27 via regulation of the AKT and STAT3 pathway. Conclusion: The expression of EXOSC5 is upregulated and correlated with tumorigenesis and poor prognosis of GC. EXOSC5 increases GC proliferation partly through activating AKT and STAT3 pathways.
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Gastric cancer (GC) is one of the most common malignant tumors with poor outcomes. Identification of new therapeutic targets is urgently needed. Accumulating evidence has shown that anti-silencing function 1b (ASF1b) contributes to the progression in multiple cancer types. However, detailed mechanisms of ASF1b tumorigenesis in gastric cancer remain elusive. This study showed that ASF1b was upregulated in GC tissues and remarkably correlated with TNM stage, histological grade and poor prognosis of GC. We induced down and up-regulation of ASF1b in GC cell lines and monitored the changes in their biological behavior. Furthermore, loss of ASF1b was efficient to suppress subcutaneous xenograft tumor growth in vivo. We demonstrate that ASF1b is involved in regulation of cell cycle and PI3K/AKT/mTOR signaling through experiments and database analysis. Mechanistically, ASF1b promoted the proliferation, migration and invasion of GC cells. Taken together, this study highlights the role of ASF1b, which provided new insights into the underlying mechanism of progression and metastasis in GC for the first time.
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Therapies for patients with advanced esophageal squamous cell carcinoma (ESCC) are limited and accompanied by dismal prognosis. Here we use ESCC cell line K30 and TE-1 to investigate the antitumor efficacy of cisplatin plus anti-PD-1 antibody. Enhanced antitumor effects and increased CD8+ tumor-infiltrating lymphocytes of combination therapy were observed in TE-1 cells bearing humanized mice model. Lower cell viability and more cell apoptosis were found in the combination therapy in vitro. We next analyzed clinical data from patients with advanced ESCC received cisplatin-based chemotherapy plus an anti-PD-1 antibody (Tislelizumab or Sintilimab) as first line therapy from two clinical trials (NCT03469557, NCT03748134). With the response rate of 81.8%, duration of response of 15.2 months, median progression-free survival of 15.5 months, median overall survival of 21.5 months and manageable toxicity in patients with advanced ESCC, we demonstrated that cisplatin-based chemotherapy plus anti-PD-1 antibody is an effective and safe option. We further confirmed sublethal cisplatin could induce PD-L1 expression in ESCC cells and cisplatin-treated ESCC cells suppressed the activation and function of immune cells while the addition of sintilimab prevented this process. These results highlight the effectiveness of cisplatin combining with anti-PD-1 antibody in patients with advanced ESCC, revealed its capability to promote the PD-L1 expression in ESCC cells and act synergistically with anti-PD-1 antibody to restore exhausted immune cells activities, thus providing a theoretical basis for further explorations in the mechanism of the combination treatment of cisplatin-based chemotherapy with immune checkpoint inhibitors in ESCC.
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Gastric cancer (GC) is one of the most prevalent digestive malignancies. A great number of patients at first visit or post curative resections are diagnosed with widespread metastasis within the peritoneal cavity. Overwhelming evidence has demonstrated that exosomes, a variety of biologically functional extracellular vesicles comprising active factors, mediate the progression and metastasis of GC. Although the regulatory mechanisms of exosomes remain fairly elusive, they are responsible for intercellular communication between tumor cells and normal stroma, cancer-related fibroblasts, immune cells within the primary tumor and metastatic niche. In this review, we provide new insight into the molecular signatures of GC-associated exosomes in reprogramming the tumor microenvironment and the subsequent promotion of peritoneal metastasis-including infiltration of the gastric wall, implantation of tumor cells onto the pre-metastatic peritoneum, and remodeling of the pre-metastatic niche. Based on this review, we hope to draw a more general conclusion for the functions of exosomes in the progression and peritoneal metastasis of GC and highlight the future perspective on strategies targeting exosomes in prognostic biomarkers and therapy for peritoneal metastasis.
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Objective: Gastric cancer (GC) is a type of highly malignant cancer. Although the diagnostic and therapeutic methods are innovating, the outcome of GC patients is still poor. Therefore, our research was carried out to explore potential molecular mechanism in the diagnosis of GC. Materials and methods: Bioinformatics analyses were used to obtain microRNA and target mRNA of interest. The expression level of miR-301a-5p and Scinderin (SCIN) mRNA were detected by quantitative real-time PCR (qRT-PCR). Western blot assay was used to investigate SCIN protein level. Cell Counting Kit-8 assay (CCK-8) and colony formation assay were used to investigate cell proliferation ability. Transwell assay was employed to examine cell motility. The interaction between miR-301a-5p and SCIN mRNA was verified by dual-luciferase reporter assay. Results: The qRT-PCR analysis revealed that the expression of miR-301a-5p was higher in gastric cancer tissues than para-cancer tissues (P<0.05). Cox regression analysis showed upregulated miR-301a-5p was associated with larger tumor size (P=0.036) and more advanced TNM stage (P=0.048). The Kaplan-Meier analysis showed a correlation between increased miR-301a-5p expression and shorter overall survival (OS)(P=0.018). By using bioinformatic analysis, SCIN was predicted as one of the targets of miR-301a-5p. Overexpressing miR-301a-5p promoted proliferation and motility of GC cells while knockdown of SCIN exhibited the same performance. Further, we verified the alteration of miR-301a-5p and SCIN expression level could affect the epithelial-mesenchymal transition (EMT) progression on GC cells via STAT3 and NF-κB signaling. Conclusion: Highly expressed miR-301a-5p was associated with aggressiveness of GC. Upregulation of miR-301a-5p promoted malignant phenotype of GC by targeting SCIN. The present results indicated miR-301a-5p might be a promising molecule in the prognosis of GC.