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1.
Biochem Biophys Res Commun ; 498(3): 409-415, 2018 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-29452091

RESUMEN

Exosomes are membrane-bound, virus-sized vesicles present in circulating blood. Tumor cells are avid producers of exosomes, which are thought to mimic molecular features of parent tumor cells. T-cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) is a the next-generation immune checkpoint that can be activated by its ligand Galectin-9 to negatively regulate the anti-tumor immune response. However, the characteristics of plasma exosomal Tim-3 and Galectin-9 (Exo-T/G) in cancer remained unknown. This study was conducted to investigate the expression patterns and clinical value of plasma exosomal total protein (Exo-pro) and Exo-T/G in non-small cell lung cancer (NSCLC). Plasma was collected from 103 NSCLC patients including 60 early stages and 43 advanced stages disease samples as well as 56 healthy subjects. Exosomes were isolated from plasma by commercial exosome precipitation solution and identified by western blotting of CD63 and transmission electron microscopy. Exo-pro concentration was measured by the BCA assay. Enzyme-linked immunosorbent assay was used to quantify Exo-T/G. Additionally, 34 NSCLC samples were applied to directly detect plasma TIM-3 (Plas-T) and Galectin-9 (Plas-G). Our results showed that Exo-pro, Exo-T, and Exo-G were significantly increased in NSCLC plasma compared to that in the healthy samples. High levels of Exo-T and Exo-G were all positively correlated with several malignant parameters, including larger tumor size, advanced stages, and more distant metastasis. High levels of Exo-pro and Exo-T were also correlated with more lymph node metastasis. Additionally, plasma from lung squamous cell carcinoma showed higher Exo-T and Exo-G compared with that from lung adenocarcinoma. ALK-positive patients showed to have decreased Exo-T and Exo-G levels. Pearson's correlation analysis revealed a significant correlation between Exo-pro and Exo-T/G, Exo-T and Exo-G, Exo-T and Plas-T, Exo-G and Plas-G, and Plas-T and Plas-G. Together, our data revealed that Exo-pro, especially Exo-T and Exo-G could be potential biomarkers for NSCLC. Further studies focusing on pure tumor-derived exosomes isolated from plasma were needed.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Exosomas/genética , Galectinas/genética , Receptor 2 Celular del Virus de la Hepatitis A/genética , Neoplasias Pulmonares/genética , Transcriptoma , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Cohortes , Femenino , Galectinas/sangre , Regulación Neoplásica de la Expresión Génica , Receptor 2 Celular del Virus de la Hepatitis A/sangre , Humanos , Pulmón/patología , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad
2.
Cell Oncol (Dordr) ; 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-39141315

RESUMEN

PURPOSE: Dysfunctional lymphangiogenesis is pivotal for various pathological processes including tumor lymph node metastasis which is a crucial cause of therapeutic failure for ESCC. In this study, we aim to elucidate the molecular mechanisms and clinical relevance of Zinc-finger protein ZNF468 in lymphangiogenesis and lymphatic metastasis in ESCC. METHODS: Immunohistochemistry, Western blot, Kaplan-Meier plotter analysis and Gene Set Enrichment Analysis were preformed to detect the association of ZNF468 with lymphangiogenesis and poor prognosis in ESCC patients. Foot-pads lymph node metastasis model, tube formation assay, 3D-culture assay and invasion assay were preformed to verify the effect of ZNF468 on lymphangiogenesis and lymph node metastasis. CUT&Tag analysis, immunoprecipitation and mass spectrometry analysis and ChIP-PCR assay were preformed to study the molecular mechanisms of ZNF468 in lymphangiogenesis. RESULTS: We found that ectopic expression of ZNF468 was correlated with higher microlymphatic vessel density in ESCC tissues, leading to poorer prognosis of ESCC patients. ZNF468 enhanced the capacity of lymphangiogenesis and promoted lymphatic metastasis in ESCC both in vitro and in vivo. However, silencing ZNF468 reversed these phenotypes in ESCC. Mechanically, we demonstrated that ZNF468 recruits the histone modification factors (PRMT1/HAT1) to increase the levels of H4R2me2a and H3K9ac, which then leads to the recruitment of the transcription initiation complex on the VEGF-C promoter, ultimately promoting the upregulation of VEGF-C transcription. Strikingly, the promoting effect of lymphatic metastasis induced by ZNF468 in ESCC was abrogated by targeting PRMT1 using Arginine methyltransferase inhibitor-1 or silencing VEGF-C. Furthermore, we found that the activation of PI3K/AKT and ERK1/2 signaling is required for ZNF468-medicated lymphatic metastasis in ESCC. Importantly, the clinical relevance between ZNF468 and VEGF-C were confirmed not only in ESCC samples and but also in multiple cancer types. CONCLUSION: Our results identified a precise mechanism underlying ZNF468-induced epigenetic upregulation of VEGF-C in facilitating lymphangiogenesis and lymph node metastasis of ESCC, which might provide a novel prognostic biomarker and potential therapeutic for ESCC patients.

3.
Cell Death Discov ; 10(1): 45, 2024 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-38267442

RESUMEN

Ferroptosis represents a distinct form of programmed cell death triggered by excessive iron accumulation and lipid peroxidation-induced damage. This mode of cell death differentiates from classical programmed cell death in terms of morphology and biochemistry. Ferroptosis stands out for its exceptional biological characteristics and has garnered extensive research and conversations as a form of programmed cell death. Its dysfunctional activation is closely linked to the onset of diseases, particularly inflammation and cancer, making ferroptosis a promising avenue for combating these conditions. As such, exploring ferroptosis may offer innovative approaches to treating cancer and inflammatory diseases. Our review provides insights into the relevant regulatory mechanisms of ferroptosis, examining the impact of ferroptosis-related factors from both physiological and pathological perspectives. Describing the crosstalk between ferroptosis and tumor- and inflammation-associated signaling pathways and the potential of ferroptosis inducers in overcoming drug-resistant cancers are discussed, aiming to inform further novel therapeutic directions for ferroptosis in relation to inflammatory and cancer diseases.

4.
Med Oncol ; 40(10): 290, 2023 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-37658961

RESUMEN

Chemo-resistance has been identified as a crucial factor contributing to tumor recurrence and a leading cause of worse prognosis in patients with ESCC. Therefore, unravel the critical regulators and effective strategies to overcome drug resistance will have a significant clinical impact on the disease. In our study we found that RNF149 was upregulated in ESCC and high RNF149 expression was associated with poor prognosis with ESCC patients. Functionally, we have demonstrated that overexpression of RNF149 confers CDDP resistance to ESCC; however, inhibition of RNF149 reversed this phenomenon both in vitro and in vivo. Mechanistically, we demonstrated that RNF149 interacts with PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2) and induces E3 ligase-dependent protein degradation of PHLPP2, substantially activating the PI3K/AKT signalling pathway in ESCC. Additionally, we found that inhibition of PI3K/AKT signalling pathway by AKT siRNA or small molecule inhibitor significantly suppressed RNF149-induced CDDP resistance. Importantly, RNF149 locus was also found to be amplified not only in ESCC but also in various human cancer types. Our data suggest that RNF149 might function as an oncogenic gene. Targeting the RNF149/PHLPP2/PI3K/Akt axis may be a promising prognostic factor and valuable therapeutic target for malignant tumours.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/genética , Cisplatino/farmacología , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Recurrencia Local de Neoplasia , Proteína Fosfatasa 2 , Fosfoproteínas Fosfatasas/genética
5.
Front Microbiol ; 12: 649978, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34046021

RESUMEN

Understanding the evolution of microorganisms and metabolites during wine fermentation is essential for controlling its production. The structural composition and functional capacity of the core microbiota determine the quality and quantity of fruit wine. Nanfeng tangerine wine fermentation involves a complex of various microorganisms and a wide variety of metabolites. However, the microbial succession and functional shift of the core microbiota in this product fermentation remain unclear. Therefore, high-throughput sequencing (HTS) and headspace-gas chromatography-mass spectrometry (HS/GC-MS) were employed to reveal the core functional microbiota for the production of volatile flavors during spontaneous fermentation (SF) and inoculated fermentation (IF) with Saccharomyces cerevisiae of Nanfeng tangerine wine. A total of 13 bacterial and 8 fungal genera were identified as the core microbiota; Lactobacillus and Acetobacter were the dominant bacteria in SF and IF, respectively. The main fungal genera in SF and IF were Hanseniaspora, Pichia, and Saccharomyces with a clear succession. In addition, the potential correlations analysis between microbiota succession and volatile flavor dynamics revealed that Lactobacillus, Acetobacter, Hanseniaspora, and Saccharomyces were the major contributors to the production of the volatile flavor of Nanfeng tangerine wine. The results of the present study provide insight into the effects of the core functional microbiota in Nanfeng tangerine wine and can be used to develop effective strategies for improving the quality of fruit wines.

6.
Oncol Rep ; 40(4): 1971-1984, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30106450

RESUMEN

Gasdermin D (GSDMD) is a newly discovered pyroptosis executive protein, which can be cleaved by inflammatory caspases and is essential for secretion of IL­1ß, making it a critical mediator of inflammation. However, the precise role of GSDMD in carcinogenesis remains nearly unknown. Considering the vital role of inflammation in tumorigenesis, we investigated the biological function of GSDMD in non­small cell lung cancer (NSCLC). Our study demonstrated that the GSDMD protein levels were significantly upregulated in NSCLC compared to these levels in matched adjacent tumor specimens. Higher GSDMD expression was associated with aggressive traits including larger tumor size and more advanced tumor-node-metastasis (TNM) stages. In addition, high GSDMD expression indicated a poor prognosis in lung adenocarcinoma (LUAD), but not in squamous cell carcinoma (LUSC). Knockdown of GSDMD restricted tumor growth in vitro and in vivo. Notably, intrinsic and extrinsic activation of pyroptotic (NLRP3/caspase­1) signaling in GSDMD­deficient tumor cells induced another type of programmed cell death (apoptosis), instead of pyroptosis. GSDMD depletion activated the cleavage of caspase­3 and PARP, and promoted cancer cell death via intrinsic mitochondrial apoptotic pathways. In addition, co­expression analyses indicated a correlation between GSDMD and EGFR/Akt signaling. Collectively, our results revealed a crosstalk between pyroptotic signaling and apoptosis in tumor cells. Knockdown of GSDMD attenuated tumor proliferation by promoting apoptosis and inhibiting EGFR/Akt signaling in NSCLC. In conclution, GSDMD is an independent prognostic biomarker for LUAD.


Asunto(s)
Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/secundario , Proliferación Celular , Receptores ErbB/metabolismo , Neoplasias Pulmonares/patología , Mitocondrias/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/secundario , Adenocarcinoma/terapia , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/terapia , Estudios de Casos y Controles , Caspasas/metabolismo , Movimiento Celular , Receptores ErbB/genética , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Metástasis Linfática , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/patología , Proteínas de Neoplasias/genética , Proteínas de Unión a Fosfato , Pronóstico , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Oncotarget ; 8(42): 73258-73270, 2017 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-29069867

RESUMEN

BACKGROUND: To assess the efficacy profile of erlotinib-based doublet targeted therapy compared with erlotinib monotherapy for previously treated patients with advanced NSCLC, a meta-analysis was performed. PATIENTS AND METHODS: We rigorously searched PubMed, Embase, Cochrane and meeting proceedings. Phase II/III randomized trials reporting on the efficacy of erlotinib-doublet therapy versus single-agent therapy were selected. We estimated the HR for OS, PFS and the RR for ORR, DCR, 1-year SR. Phases of trials, targeted signaling pathways, EGFR-status and KRAS- status were included in subset analysis. RESULTS: 24 studies involving 6,196 patients were eligible. In general, the combination targeted therapy significantly improved PFS, ORR and DCR. There was also a trend showing improved OS and 1-year SR in doublets group, though it was not statistically significant. Subgroup analysis suggested PFS improvement in EGFR wild-type, KRAS mutant, KRAS wild-type populations. Moreover, patients treated with anti-angiogenesis or anti-MET targeted agent revealed a significant benefit in PFS. CONCLUSION: In patients with advanced NSCLC, erlotinib-doublets target therapy (specially combination with anti-angiogenesis and anti-MET targeted agents) was associated with a statistically significantly longer PFS, greater ORR and DCR, but the combination did not improve OS and 1-year SR compared with erlotinib alone.

8.
Transl Lung Cancer Res ; 6(1): 68-75, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28331826

RESUMEN

The incidence of pulmonary ground-glass opacity (GGO) lesions is increasing as a result of the widespread use of multislice spiral computed tomography (CT) and the low-dose CT screening for lung cancer detection. Besides benign lesions, GGOs can be a specific type of lung adenocarcinomas or their preinvasive lesions. Evaluation of pulmonary GGO and investigation of the correlation between CT imaging features and lung adenocarcinoma subtypes or driver genes can be helpful in confirming the diagnosis and in guiding the clinical management. Our review focuses on the pathologic characteristics of GGO detected at CT, involving histopathology and molecular pathology.

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