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1.
Cell Signal ; 123: 111338, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39117252

RESUMEN

BACKGROUND: PDAC, also known as pancreatic ductal adenocarcinoma, is often diagnosed at a late stage due to nonspecific symptoms and a distinct lack of reliable biomarkers for timely diagnosis. Ferroptosis, a novel non-apoptotic cell death mode discovered in recent years, is strongly linked to the progression of PDAC and the evasion of the immune system. The objective of this study is to discover a novel ceRNA biomarker associated with ferroptosis and investigate its possible molecular mechanisms and therapeutic potential in PDAC. METHODS: Based on the FerrDb and TCGA databases, the R survival package was used to screen for ferroptosis-related mRNAs associated with PDAC prognosis. The ferroptosis-related ceRNA network was identified by miRTarBase, miRNet, and starBase and visualized using Cytoscape. The LASSO regression analysis was used to build a risk model associated with ceRNA. Additionally, we investigated the correlation between the ceRNA axis and the infiltration of immune cells in PDAC by employing the ssGSEA algorithm. Spearman correlation analysis was used to investigate the association between the ceRNA network and the expression levels of immune checkpoint genes in PDAC. The prediction of potential medications for PAAD patients with high risk scores was conducted using the R package oncoPredict and the Genomics of Drug Sensitivity in Cancer (GDSC) repository. Expression levels of LINC02535 in clinical specimens and PDAC cell lines were determined using qRT-PCR. CCK-8, colony formation, EdU, wound healing, and transwell assays were performed to assess the impact of reducing LINC02535 on the growth, migration, and invasion of PDAC cell lines BxPC3 and PANC1. RESULTS: We first discovered a new LINC02535/miR-30c-5p/EIF2S1 axis associated with ferroptosis and created a prognostic nomogram for predicting overall survival. Meanwhile, the risk scores of the LINC02535/miR-30c-5p/EIF2S1 axis associated with ferroptosis were linked to immune subtypes in PDAC. The high immune infiltration subtype exhibited elevated ceRNA risk scores and EIF2S1 expression. The correlation analysis revealed a positive correlation between ceRNA risk scores and four immune cells, namely Activated CD4 T cell, Memory B cell, Neutrophil, and Type 2 T helper cell, as well as four immune checkpoint genes, namely CD274, HAVCR2, PDCD1LG2, and TIGIT. The analysis of drug sensitivity indicated that individuals with a high-risk score may exhibit greater sensitivity to inhibitors targeting MEK1/2 compared to those with a low-risk score. In our validation experiments, it was observed that the expression of LINC02535 was increased in both PDAC tissues and cell lines. Additionally, the inhibition of LINC02535 resulted in decreased proliferation, migration, and invasion of PDAC cells. Rescue experiments demonstrated that LINC02535 promoted PDAC cell growth and metastasis by upregulating EIF2S1 expression. CONCLUSION: To summarize, a novel ferroptosis-associated LINC02535/miR-30c-5p/EIF2S1 ceRNA network for PDAC patients was established. The analysis of this network's functionality offers potential insights for clinical decision-making and the advancement of precision medicine.


Asunto(s)
Biomarcadores de Tumor , Carcinoma Ductal Pancreático , Ferroptosis , Regulación Neoplásica de la Expresión Génica , MicroARNs , Neoplasias Pancreáticas , ARN Largo no Codificante , Humanos , Ferroptosis/genética , MicroARNs/metabolismo , MicroARNs/genética , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Pronóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/inmunología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Progresión de la Enfermedad , Línea Celular Tumoral
2.
J Gastroenterol Hepatol ; 39(8): 1684-1694, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38747068

RESUMEN

BACKGROUND AND AIM: The impact of cholecystectomy, which blocks the cholecystohepatic shunt pathway (CHSP), on the prognosis of patients with hepatocellular carcinoma (HCC) is unclear. Hepatic secondary bile acids (BAs) inhibit natural killer T (NKT) cell-mediated immunity against HCC, and the regulation of homeostasis of hepatic secondary BAs is controlled by the CHSP. However, the influence of CHSP on NKT cell-mediated immunity against HCC remains unclear. METHODS: The clinical data of hospitalized patients undergoing HCC resection were collected. Meanwhile, an in situ HCC mouse model was established, and the CHSP was augmented using oleanolic acid (OA). RESULTS: After 1:1 propensity score matching, Cox regression analysis revealed that cholecystectomy was an independent risk factor for HCC recurrence after hepatectomy (P = 0.027, hazard ratio: 1.599, 95% confidence interval: 1.055-2.422). Experimentally, when OA enhanced CHSP, a significant decrease was observed in the accumulation of secondary BAs in the livers of mice. Additionally, a significant increase was observed in the levels of C-X-C ligand 16 and interferon γ in the serum and tumor tissues. Further, the percentage of C-X-C receptor 6 (+) NKT cells in the tumor tissues increased significantly, and the growth of liver tumors was inhibited. CONCLUSIONS: This clinical study revealed that cholecystectomy promoted the recurrence after radical hepatectomy in patients with HCC. Preserving the normal-functioning gallbladder as much as possible during surgery may be beneficial to the patient's prognosis. Further investigation into the mechanism revealed that CHSP enhanced NKT cell-mediated immunity against HCC by reducing the hepatic accumulation of secondary BAs.


Asunto(s)
Ácidos y Sales Biliares , Carcinoma Hepatocelular , Neoplasias Hepáticas , Células T Asesinas Naturales , Animales , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/cirugía , Células T Asesinas Naturales/inmunología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/cirugía , Ácidos y Sales Biliares/metabolismo , Masculino , Humanos , Femenino , Colecistectomía , Modelos Animales de Enfermedad , Ratones , Hepatectomía , Persona de Mediana Edad , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacología , Hígado/metabolismo , Ratones Endogámicos C57BL , Inmunidad Celular , Recurrencia Local de Neoplasia/prevención & control , Interferón gamma/metabolismo , Factores de Riesgo , Anciano
3.
Cell Signal ; 116: 111033, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38182068

RESUMEN

BACKGROUND: Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is an aggressive disease with an overall poor prognosis. Pancreatitis is a major risk factor for the development of PDAC. Due to the lack of reliable and accurate biomarkers, the diagnosis, treatment, and prognosis of PDAC face great challenges. It is of great significance to elucidate the pathogenesis of PDAC and explore novel inflammatory biomarkers. METHODS: We identified E3 ubiquitin ligases associated with pancreatic inflammation by combining multiple GEO datasets and UbiNet 2.0, and integrating the WGCNA algorithm and Limma R package. A risk score model for PDAC patients was established by using LASSO regression. We investigated the correlation between FBXW11 and immune cell infiltration using CIBERSORT, mMCP-counter, ImmuCellAI-mouse, QUANTISEQ, and TIMER algorithms, based on GEO, ArrayExpress, and TCGA datasets. We used Ubibrowser 2.0 to predict potential substrates for FBXW11. WikiPathway, MSigDB Hallmark, and Elsevier pathway analysis of FBXW11 key substrates were also performed using the EnrichR database. We detected protein expression through IHC, immunofluorescence, and western blot in the cerulein-induced acute pancreatitis mouse model. RESULTS: We first identified that FBXW11 exhibited a clear tendency to gradually increase in normal, pancreatitis, and PDAC patients. The validation analysis revealed that the FBXW11 protein exhibited significantly high expression in cerulein-induced acute pancreatitis mice, with its distribution primarily observed in the cytoplasm. Simultaneously, we developed a risk model utilizing the genes associated with FBXW11 to forecast the outcome of patients with PDAC and the likelihood of pancreatitis advancing to pancreatic cancer. Functional analysis showed that FBXW11, as a novel inflammatory biomarker, had a significant positive correlation with macrophage infiltration and the NF-κB signaling pathway. Finally, the western blot assay of the NF-κB signaling pathway in pancreatic tissues demonstrated that high activation of NF-κB was correlated with high expression of FBXW11. CONCLUSIONS: Our research not only provides evidence for FBXW11 as a novel inflammatory biomarker but also provides new insights into the research and clinical treatment of pancreatic cancer.


Asunto(s)
Neoplasias Pancreáticas , Pancreatitis , Animales , Humanos , Ratones , Enfermedad Aguda , Proteínas con Repetición de beta-Transducina , Biomarcadores , Ceruletida , FN-kappa B , Transducción de Señal , Ubiquitina-Proteína Ligasas
4.
Transl Oncol ; 34: 101683, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37224767

RESUMEN

BACKGROUND: ALKBH5 belongs to the ALKB family consists of a Fe (II) and a-ketoglutarate-dependent dioxygenase. ALKBH5 directly catalyzes the oxidative demethylation of m6A-methylated adenosine. ALKBH5 involves in tumorigenesis and tumor progression, and is often dysregulated in a wide range of cancers, including colorectal cancer. Emerging evidence indicates that the expression of ALKBH5 is associated with the abundance of infiltrating immune cells in the microenvironment. However, how ALKBH5 affects immune cell infiltration in the microenvironment in colorectal cancer (CRC) has not been reported. The aim of this study was to identify how the expression of ALKBH5 affects the biological behaviors of CRC cell lines and regulates the effects on infiltrating CD8+ T cells in CRC microenvironment with its specific mechanism. METHODS: Firstly, the transcriptional expression profiles of CRC were downloaded from TCGA database and integrated via R software (4.1.2). Between CRC and normal colorectal tissues, ALKBH5 mRNA expressions were compared (Wilcoxon rank-sum). We further identified the expression levels of ALKBH5 in CRC tissues and cell lines through quantitative PCR, western blot, and immunohistochemistry. Then, how ALKBH5 affects the biological behaviors of CRC cells were confirmed by gain- and loss-of-function analysis. Furthermore, the relationship between ALKBH5 level and 22 tumor-infiltrating immune cells was examined through CIBERSORT in R software. Furthermore, we explored the correlation between ALKBH5 expression and tumor-infiltrated CD8+, CD4+ and regulatory T cells by utilizing the TIMER database. Finally, the association between chemokines and CD8+ T cells infiltration in CRC was analyzed using GEPIA online database. qRT-PCR, WB and IHC were used to further determine the effect of ALKBH5 on NF-κB-CCL5 signaling axis and CD8+ T cells infiltration. RESULTS: Clinically, ALKBH5 expression was downregulated in CRC and low levels of ALKBH5 expression were correlated with poor overall survival (OS). Functionally, overexpression of ALKBH5 reduced the proliferation, migration and invasion of CRC cells, and vice versa. Overexpression of ALKBH5 suppresses NF-κB pathway, thus reduces CCL5 expression and promotes CD8+ T cells infiltration in CRC microenvironment. CONCLUSIONS: ALKBH5 is poorly expressed in CRC, and overexpression of ALKBH5 attenuates CRC malignant progression by inhibiting CRC cell proliferation, migration, invasion and promoting CD8+ T cells infiltration in the tumor microenvironment through NF-κB-CCL5 axis.

5.
Am Surg ; 89(6): 2979-2981, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35544955

RESUMEN

Castleman disease (CD) is a lymphoproliferative disorder that rarely occurs in the pancreas. We reported a 46-year-old man was admitted to our hospital due to recurrent minor epigastric pain for 7 days. The abdominal enhanced CT showed irregular foci in the body of the pancreas with abundant blood supply considered a neuroendocrine tumor. The patient was subsequently diagnosed with pancreatic neuroendocrine tumor by an ultrasound-guided fine needle aspiration biopsy. Therefore, he underwent an open pancreatic mass resection. The ultimate diagnosis was CD and belonged to hyaline vascular type based on the postoperative pathology. After a 13-month follow-up, no recurrence of abdominal pain or lesions was observed. This case suggests that fine needle aspiration biopsy is not conclusive and unsuitable for pancreatic CD and highlights the importance of routine pathology due to the absence of typical signs and symptoms.


Asunto(s)
Enfermedad de Castleman , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Masculino , Humanos , Persona de Mediana Edad , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/cirugía , Tumores Neuroendocrinos/patología , Enfermedad de Castleman/diagnóstico , Enfermedad de Castleman/cirugía , Enfermedad de Castleman/patología , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Páncreas/diagnóstico por imagen , Dolor Abdominal , Errores Diagnósticos
6.
Cells ; 11(23)2022 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-36497182

RESUMEN

Glutamine metabolism is critical both for the proliferation of cancer cells and the activation of CD8T cells to kill cancer cells. We aim to explore the relationship between the glutamine metabolism of CD8T cells and cancer cells and tumor immunity in the tumor microenvironment. In a TCGA cohort, we found that patients with high scores of glutamine-metabolism-related genes showed poor prognoses, and that a high score of glutamine-metabolism-related genes was an independent risk factor for HCC patients. In single-cell RNA-seq data, we found that, in some patients, the glutamine metabolism gene scores of tumor cells were significantly higher than those of CD8T cells, while decreased ratios of CD8-Tef-GZMA and suppressed tumor-killing activity of CD8-Tef-APOC2 were observed. A further genetic dynamics pseudotime analysis suggested that immune remodeling of these two subpopulations was accompanied by metabolic reprogramming. CD8-Tef-APOC2 in the dominant group tended to metabolize exogenous lipids, while the metabolic program of CD8-Tef-GZMA in the nondominant group was characterized by amino acid and endogenous lipid synthesis. In addition, we found that the glutamine metabolism inhibitor JHU083 promoted the proliferation of CD8T cells and improved the efficacy of PD-1 blockers. We proposed a new tool to quantify the glutamine partitioning between tumor cells and CD8T cells, through which the unique immune microenvironment could be identified at the transcriptome level. Furthermore, the simultaneous destruction of the glutamine metabolism in tumor cells and CD8T cells facilitated the enrichment of tumor-infiltrating CD8T cells and enhanced the efficacy of immunotherapy.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Glutamina/metabolismo , Neoplasias Hepáticas/patología , Linfocitos T CD8-positivos , Microambiente Tumoral
7.
World J Gastrointest Surg ; 14(5): 514-520, 2022 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-35734619

RESUMEN

BACKGROUND: Castleman disease is an uncommon nonclonal lymphoproliferative disorder, which frequently mimics both benign and malignant abnormalities in several regions. Depending on the number of lymph nodes or regions involved, Castleman disease (CD) varies in diagnosis, treatment and prognosis. It rarely occurs in the pancreas alone without any distinct clinical feature and tends to be confused with pancreatic paraganglioma (PGL), neuroendocrine tumors (NETs), and primary tumors, thus impeding proper diagnosis and treatment. CASE SUMMARY: A 28-year-old woman presented with a lesion on the neck of the pancreas, detected by ultrasound during a health examination. Physical examination and laboratory findings were normal. The mass showed hypervascularity on enhanced computed tomography (CT), significantly increased 18F-fluorodeoxyglucose uptake on positron emission tomography (PET)/CT, and slightly increased somatostatin receptor (SSTR) expression on 68Ga-DOTATATE PET/CT, suggesting no distant metastases and subdiagnoses such as pancreatic PGL, NET, or primary tumor. Intraoperative pathology suggested lymphatic hyperplasia, and only simple tumor resection was performed. The patient was diagnosed with the hyaline vascular variant of CD, which was confirmed by postoperative immunohistochemistry. The patient was discharged successfully, and no recurrence was observed on regular review. CONCLUSION: High glucose uptake and slightly elevated SSTR expression are potentially new diagnostic features of CD of the pancreas.

8.
Acta Radiol Open ; 11(3): 20584601221085514, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35368406

RESUMEN

Background: Both transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) are effective methods for the treatment of recurrent hepatocellular carcinoma (RHCC). Thus far, it is unclear which method is more satisfactory in short- and long-term survival benefits. Purpose: To compare the overall survival (OS) and complications of TACE and RFA used for the management of RHCC. Material and Methods: A literature search was carried out using PubMed, the Cochrane Library and, Embase databases, and Google Scholar, keywords including "RHCC," "TACEC," and "RFA" with a cutoff date of 30 April 2021. Used Review Manager software was to calculate short- and long-term OS. The clinical outcomes are major complications and complete response (CR). Results: Finally, nine clinical trials met the research standard, including 1326 subjects, of which 518 received RFA and 808 received TACE. The analysis showed that patients who underwent RFA had significantly higher 1-, 3-, and 5-year OS (OR1-year = 1.92, 95% confidence interval (CI) = 1.27-2.91, p = .002; OR3-year = 1.64, 95% CI = 1.30-2.08, p <.0001; OR5-year = 3.22, 95% CI = 1.34-7.72, p=.009). Besides, the patients who chose RFA had an obvious higher rate of CR than those receiving TACE (OR = 33.75, 95% CI = 1.73-658.24, p = .002). However, the major complications were consistency between these two groups. Conclusion: Our study discovered that RFA had greater CR and incidence in both the short-term and long-term OS than TACE. In addition, obvious difference was not found in major complications in these two methods.

9.
Front Immunol ; 13: 1095915, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36605219

RESUMEN

Hepatocellular carcinoma (HCC) is the most common type of liver malignancy with a high incidence and mortality rate. Previous in vitro and in vivo studies have confirmed that liver sinusoidal endothelial cells (LSEC) secrete CXCL16, which acts as a messenger to increase the hepatic accumulation of CXCR6+ natural killer T (NKT) cells and exert potent antitumor effects. However, evidence for this process in humans is lacking and its clinical significance is still unclear. In this study, by dissecting the human HCC single-cell RNA-seq data, we verified this process through cellphoneDB. NKT cells in patients with high expression of CXCL16 exhibited a higher activation state and produced more interferon-γ (IFN-γ) compared with those with low expression. We next investigated the signaling pathways between activated (CD69 high) and unactivated NKT cells (CD69 low) using NKT cell-developmental trajectories and functional enrichment analyses. In vivo experiments, we found that farnesoid X receptor agonist (obeticholic acid) combined with the takeda G protein coupled receptor 5 antagonist (5ß-cholanic acid 3) exhibited significant tumor suppressive effects in the orthotopic liver tumor model and this result may be related to the CXCL16/CXCR6 axis. In conclusion, our study provides the basis and potential strategies for HCC immunotherapy based on NKT cells.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Células Endoteliales/metabolismo , Receptores CXCR6/metabolismo , Ratones Endogámicos C57BL , Quimiocina CXCL16
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