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Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment.
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Neoplasias de la Mama , Proliferación Celular , Histonas , Animales , Femenino , Humanos , Ratones , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glucólisis/genética , Histonas/metabolismo , L-Lactato Deshidrogenasa/metabolismo , L-Lactato Deshidrogenasa/genética , Lactato Deshidrogenasa 5/metabolismo , Lactato Deshidrogenasa 5/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Metástasis de la Neoplasia , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Canales de Potasio de Dominio Poro en Tándem/genética , Pronóstico , Regulación hacia Arriba/genéticaRESUMEN
Immune evasion contributes to cancer growth and progression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. The programmed death protein 1 (PD-1) and programmed cell death ligands (PD-Ls) are considered to be the major immune checkpoint molecules. The interaction of PD-1 and PD-L1 negatively regulates adaptive immune response mainly by inhibiting the activity of effector T cells while enhancing the function of immunosuppressive regulatory T cells (Tregs), largely contributing to the maintenance of immune homeostasis that prevents dysregulated immunity and harmful immune responses. However, cancer cells exploit the PD-1/PD-L1 axis to cause immune escape in cancer development and progression. Blockade of PD-1/PD-L1 by neutralizing antibodies restores T cells activity and enhances anti-tumor immunity, achieving remarkable success in cancer therapy. Therefore, the regulatory mechanisms of PD-1/PD-L1 in cancers have attracted an increasing attention. This article aims to provide a comprehensive review of the roles of the PD-1/PD-L1 signaling in human autoimmune diseases and cancers. We summarize all aspects of regulatory mechanisms underlying the expression and activity of PD-1 and PD-L1 in cancers, including genetic, epigenetic, post-transcriptional and post-translational regulatory mechanisms. In addition, we further summarize the progress in clinical research on the antitumor effects of targeting PD-1/PD-L1 antibodies alone and in combination with other therapeutic approaches, providing new strategies for finding new tumor markers and developing combined therapeutic approaches.
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Antígeno B7-H1 , Neoplasias , Receptor de Muerte Celular Programada 1 , Humanos , Neoplasias/metabolismo , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/etiología , Neoplasias/genética , Receptor de Muerte Celular Programada 1/metabolismo , Antígeno B7-H1/metabolismo , Animales , Transducción de Señal , Regulación Neoplásica de la Expresión GénicaRESUMEN
PURPOSE: To investigate the dose rate dependence of MapCHECK3 and its influence on measurement accuracy, as well as the effect of dose rate correction. MATERIALS AND METHODS: The average and instantaneous dose rate dependence of MapCHECK2 and MapCHECK3 were studied. The accuracy of measurements was investigated where the dose rate differed significantly between dose calibration of the MapCHECK and the measurement. Measurements investigated include: the central axis dose for different fields at different depths, off-axis doses outside the field, and off-axis doses along the wedge direction. Measurements using an ion chamber were taken as the reference. Exponential functions were fit to account for average and instantaneous dose rate dependence for MapCHECK3 and used for dose rate correction. The effect of the dose rate correction was studied by comparing the differences between the measurements for MapCHECK (with and without the correction) and the reference. RESULTS: The maximum dose rate dependence of MapCHECK3 is greater than 2.5%. If the dose calibration factor derived from a 10 × 10 cm2 open field at 10 cm depth was used for measurements, the average differences in central diode dose were 0.8% ± 1.0% and 1.0% ± 0.8% for the studied field sizes and measurement depths, respectively. The introduction of wedge would not only induce -1.8% ± 1.3% difference in central diode dose, but also overestimate the effective wedge angle. After the instantaneous dose rate correction, above differences can be changed to 1.9% ± 8.1%, 0.2% ± 0.1%, and 0.0% ± 0.9%. The pass rate can be improved from 98.4% to 98.8%, 98.3%-100.0%, and 96.3%-100.0%, respectively. CONCLUSION: Compared with MapCHECK2 (SunPoint1 diodes), the more pronounced dose rate dependence of MapCHECK3 (SunPoint2 diodes) should be carefully considered. To ensure highly accurate measurement, it is suggested to perform the dose calibration at the same condition where measurement will be performed. Otherwise, the dose rate correction should be applied.
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MCM4 forms the pre-replication complex (MCM2-7) with five other minichromosome maintenance (MCM) proteins. This complex binds to replication origins at G1 stage in cell cycle process, playing a critical role in DNA replication initiation. Recently, MCM4 is reported to have a complex interaction with multiple cancer progression, including gastric, ovarian and cervical cancer. Here, this study mainly focused on the expression of MCM4 and its values in lung adenocarcinoma (LUAD). MCM4 was highly expressed in LUAD tumours and cells, and had an important effect on the overall survival. Overexpression of MCM4 promoted the proliferation, and suppressed the apoptosis in LUAD cells. However, MCM4 silence led to the opposite results. In vivo, knockdown of MCM4 inhibited tumour volume and weight in xenograft mouse model. As a member of DNA helicase, knockdown of MCM4 caused cell cycle arrest at G1 stage through inducing the expression of P21, a CDK inhibitor. These findings indicate that MCM4 may be a possible new therapeutic target for LUAD in the future.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Animales , Ratones , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/genética , Componente 4 del Complejo de Mantenimiento de Minicromosoma/genética , Proteínas de Mantenimiento de Minicromosoma/genética , Proteínas de Mantenimiento de Minicromosoma/metabolismo , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/genética , BiomarcadoresRESUMEN
Currently, more than 170 modifications have been identified on RNA. Among these RNA modifications, various methylations account for two-thirds of total cases and exist on almost all RNAs. Roles of RNA modifications in cancer are garnering increasing interest. The research on m6A RNA methylation in cancer is in full swing at present. However, there are still many other popular RNA modifications involved in the regulation of gene expression post-transcriptionally besides m6A RNA methylation. In this review, we focus on several important RNA modifications including m1A, m5C, m7G, 2'-O-Me, Ψ and A-to-I editing in cancer, which will provide a new perspective on tumourigenesis by peeking into the complex regulatory network of epigenetic RNA modifications, transcript processing, and protein translation.
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Neoplasias , Procesamiento Postranscripcional del ARN , Humanos , ARN Mensajero/metabolismo , ARN/genética , ARN/metabolismo , Neoplasias/genética , MetilaciónRESUMEN
Semiconductiong polymer nanoparticles (Pdots) have a wide range of applications in biomedical fields including biomolecular probes, tumor imaging, and therapy. However, there are few systematic studies on the biological effects and biocompatibility of Pdots in vitro and in vivo. The physicochemical properties of Pdots, such as surface modification, are very important in biomedical applications. Focusing on the central issue of the biological effects of Pdots, we systematically investigated the biological effects and biocompatibility of Pdots with different surface modifications and revealed the interactions between Pdots and organisms at the cellular and animal levels. The surfaces of Pdots were modified with different functional groups, including thiol, carboxyl, and amino groups, named Pdots@SH, Pdots@COOH, and Pdots@NH2, respectively. Extracellular studies showed that the modification of sulfhydryl, carboxyl, and amino groups had no significant effect on the physicochemical properties of Pdots, except that the amino modification affected the stability of Pdots to a certain extent. At the cellular level, Pdots@NH2 reduced cellular uptake capacity and increased cytotoxicity due to their instability in solution. At the in vivo level, the body circulation and metabolic clearance of Pdots@SH and Pdots@COOH were superior to those of Pdots@NH2. The four kinds of Pdots had no obvious effect on the blood indexes of mice and histopathological lesions in the main tissues and organs. This study provides important data for the biological effects and safety assessment of Pdots with different surface modifications, which pave the way for their potential biomedical applications.
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Nanopartículas , Semiconductores , Animales , Polímeros/química , Imagen Óptica/métodosRESUMEN
N6-methyladenosine (m6A) is an extremely common and conservative posttranscriptional modification, that can specifically target and regulate the expression or stability of a series of tumor-related genes, thus playing critical roles in the occurrence and development of tumors. c-Myc is an important tumorigenic transcription factor that promotes tumorigenesis and development by mainly regulating the expression of downstream target genes. Increasing evidence shows that m6A modification, as well as abnormal expression and regulation of c-Myc, is critical molecular mechanisms driving tumorigenesis and development. Although more evidence has been uncovered about the individual roles of m6A modification or c-Myc in tumors, the interaction between m6A modification and c-Myc in tumorigenesis and development has not been systematically summarized. Therefore, this review is focused on the mutual regulation between m6A modification and c-Myc expression and stability as well as its roles in tumorigenesis and development. We also summarized the potential value of the interaction between m6A modification and m6A expression and stability in tumor diagnosis and treatment, which provides a specific reference for revealing the mechanism of tumor occurrence and development as well as clinical diagnosis and treatment.
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Adenosina/análogos & derivados , Neoplasias , Proteínas Proto-Oncogénicas c-myc/metabolismo , Adenosina/genética , Adenosina/metabolismo , Carcinogénesis , Regulación de la Expresión Génica , Humanos , Neoplasias/genética , Neoplasias/patologíaRESUMEN
BACKGROUND: Circular RNAs play an important role in tumor genesis and progression, but they have not been sufficiently studied in patients with nasopharyngeal carcinoma (NPC). METHODS: The circular RNA, circCAMSAP1, was screened in NPC cells by RNA sequencing analysis. The expression of circCAMSAP1 in NPC tissues was examined by real-time quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization. Wound-healing, transwell, MTT and flow cytometry assays, and nude mouse tumor models were used to explore the effect of circCAMSAP1 on proliferation and metastasis of NPC in vitro or in vivo. The downstream proteins regulated by circCAMSAP1 were screened using mass spectrometry. The interaction between circCAMSAP1 and the SERPINH1 mRNA was identified using the circular RNA immunoprecipitation method and the luciferase reporter assay. The interaction between SERPINH1 and transcription factor c-Myc was verified through Co-immunoprecipitation (Co-IP) and immunofluorescence. The effect of c-Myc on the generation of circCAMSAP1 was examined through RT-qPCR and chromatin immunoprecipitation. Finally, the splicing factors that promote the production of circCAMSAP1 were explored by RT-qPCR and RNA immunoprecipitation (RIP). RESULTS: We found that circCAMSAP1 was highly expressed in NPC tissues and promoted NPC proliferation and metastasis. Additionally, circCAMSAP1 promoted SERPINH1 expression through improved SERPINH1 mRNA stability by binding to the 3'-untranslated region (3'UTR) of SERPINH1. Highly expressed SERPINH1 reduced the ubiquitination-degradation rate of c-Myc, causing increased tumorigenesis. Meanwhile, c-Myc, cooperating with splicing factor 10 (SRSF10), could also promote CAMSAP1 pre-mRNA transcription and back-splicing, forming a positive feedback of circCAMSAP1 production, resulting in the proliferation and metastasis of NPC. CONCLUSIONS: Our findings revealed that circCAMSAP1 promotes NPC proliferation and metastasis by binding to the 3'UTR of SERPINH1, suggesting that the positive feedback of circCAMSAP1-SERPINH1-c-Myc may serve as a prognostic biomarker or therapeutic target in patients with NPC.
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MicroARNs , Neoplasias Nasofaríngeas , Regiones no Traducidas 3' , Animales , Carcinogénesis/genética , Proteínas de Ciclo Celular , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Retroalimentación , Regulación Neoplásica de la Expresión Génica , Proteínas del Choque Térmico HSP47 , Humanos , Ratones , MicroARNs/genética , Proteínas Asociadas a Microtúbulos , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Factores de Empalme de ARN/genética , ARN Circular/genética , Proteínas Represoras , Factores de Empalme Serina-Arginina/metabolismoRESUMEN
BACKGROUND: Circular RNAs (circRNAs) act as gene expression regulators and are involved in cancer progression. However, their functions have not been sufficiently investigated in nasopharyngeal carcinoma (NPC). METHODS: The expression profiles of circRNAs in NPC cells within different metastatic potential were reanalyzed. Quantitative reverse transcription PCR and in situ hybridization were used to detect the expression level of circPVT1 in NPC cells and tissue samples. The association of expression level of circPVT1 with clinical properties of NPC patients was evaluated. Then, the effects of circPVT1 expression on NPC metastasis were investigated by in vitro and in vivo functional experiments. RNA immunoprecipitation, pull-down assay and western blotting were performed to confirm the interaction between circPVT1 and ß-TrCP in NPC cells. Co-immunoprecipitation and western blotting were performed to confirm the interaction between ß-TrCP and c-Myc in NPC cells. RESULTS: We find that circPVT1, a circular RNA, is significantly upregulated in NPC cells and tissue specimens. In vitro and in vivo experiments showed that circPVT1 promotes the invasion and metastasis of NPC cells. Mechanistically, circPVT1 inhibits proteasomal degradation of c-Myc by binding to ß-TrCP, an E3 ubiquiting ligase. Stablization of c-Myc by circPVT1 alters the cytoskeleton remodeling and cell adhesion in NPC, which ultimately promotes the invasion and metastasis of NPC cells. Furthermore, c-Myc transcriptionally upregulates the expression of SRSF1, an RNA splicing factor, and recruits SRSF1 to enhance the biosynthesis of circPVT1 through coupling transcription with splicing, which forms a positive feedback for circPVT1 production. CONCLUSIONS: Our results revealed the important role of circPVT1 in the progression of NPC through the ß-TrCP/c-Myc/SRSF1 positive feedback loop, and circPVT1 may serve as a prognostic biomarker or therapeutic target in patients with NPC.
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Carcinoma , MicroARNs , Neoplasias Nasofaríngeas , Biomarcadores , Carcinoma/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Retroalimentación , Regulación Neoplásica de la Expresión Génica , Humanos , Ligasas/genética , MicroARNs/genética , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , ARN , Factores de Empalme de ARN/genética , ARN Circular/genética , Factores de Empalme Serina-Arginina , Proteínas con Repetición de beta-Transducina/genética , Proteínas con Repetición de beta-Transducina/metabolismoRESUMEN
Alternative splicing (AS) is a key process in which precursor RNAs produce different mature RNAs, and the disorder of AS is a key factor in promoting cancer development. Compared with coding RNA, studies on the functions of long non-coding RNAs (lncRNAs) are far from enough. In fact, lncRNA is an important participant and regulator in the process of AS. On the one hand, lncRNAs regulate cancer progression as AS products of precursor messenger RNA (mRNA), but on the other hand, precursor lncRNA generates cancer-related abnormal splicing variants through AS. In addition, lncRNAs directly or indirectly regulate the AS events of downstream target genes, thus affecting the occurrence and development of cancer. Here, we reviewed how lncRNAs regulate AS and influence oncogenesis in different ways.
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Neoplasias , ARN Largo no Codificante , Empalme Alternativo/genética , Transformación Celular Neoplásica , Humanos , Neoplasias/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN MensajeroRESUMEN
The successful treatment of human cancers by immunotherapy has been made possible by breakthroughs in the discovery of immune checkpoint regulators, including CTLA-4 and PD-1/PD-L1. However, the immunosuppressive effect of the tumor microenvironment still represents an important bottleneck that limits the success of immunotherapeutic approaches. The tumor microenvironment influences the metabolic crosstalk between tumor cells and tumor-infiltrating immune cells, creating competition for the utilization of nutrients and promoting immunosuppression. In addition, tumor-derived metabolites regulate the activation and effector function of immune cells through a variety of mechanisms; in turn, the metabolites and other factors secreted by immune cells can also become accomplices to cancer development. Immune-metabolic checkpoint regulation is an emerging concept that is being studied with the aim of restoring the immune response in the tumor microenvironment. In this review, we summarize the metabolic reprogramming of various cell types present in the tumor microenvironment, with a focus on the interaction between the metabolic pathways of these cells and antitumor immunosuppression. We also discuss the main metabolic checkpoints that could provide new means of enhancing antitumor immunotherapy.
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Inmunoterapia , Neoplasias/patología , Microambiente Tumoral , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/inmunología , Antígeno CTLA-4/metabolismo , Humanos , Células Supresoras de Origen Mieloide/citología , Células Supresoras de Origen Mieloide/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T Citotóxicos/citología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Macrófagos Asociados a Tumores/citología , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismoRESUMEN
BACKGROUND: Thrombotic complications in multiple myeloma (MM) impairs the quality of life in patients. Metformin has a certain effect on anti-thrombosis, but its role and mechanism in MM-induced thrombosis are still uncovered. Therefore, this study evaluated the effect of metformin on MM-induced thrombosis. METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to normal serum (15%), MM serum (15%), metformin (0.01 mmol/L), or MM serum, and metformin simultaneously. The expression of tissue factor (TF) in HUVECs was detected by flow cytometry and quantitative real-time polymerase chain reaction PCR (qRT-PCR). QRT-PCR was also used to determine the expressions of endothelial protein C receptor (EPCR) and miR-532. The generation of thrombin and activated protein C was measured by thrombin generation and protein C activation assays. EPCR, extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathway related protein expressions were detected by western blot. RESULTS: MM serum increased the expressions of TF and miR-532, induced thrombin generation, inhibited EPCR and protein C activation in HUVECs. And metformin could reverse the effects of MM serum on the expressions of TF, EPCR and miR-532, thrombin generation, protein C activation in HUVECs. However, miR-532 mimic reversed the effects of metformin and promoted the levels of thrombosis-related indicators in HUVECs. Moreover, metformin activated the ERK 1/2, p38 MAPK, and NF-κB pathways but miR-532 mimic suppressed the pathway activation. CONCLUSIONS: Metformin played an inhibitory effect on MM serum-induced HUVEC thrombosis, suggesting that metformin could serve as a novel antithrombotic approach for MM patients.
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Metformina , MicroARNs , Mieloma Múltiple , Trombosis , Células Cultivadas , Receptor de Proteína C Endotelial , Fibrinolíticos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Metformina/farmacología , MicroARNs/genética , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , FN-kappa B/metabolismo , Proteína C/metabolismo , Calidad de Vida , Trombina , Tromboplastina/genética , Tromboplastina/metabolismo , Trombosis/genética , Trombosis/prevención & control , Resultado del Tratamiento , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Esophageal squamous cell carcinoma (ESCC) is a common subtype of esophageal cancer with high incidence. Surgery remains the main strategy for treatment of ESCC at early stage. However, the treatment outcome is unsatisfactory. Therefore, finding new therapeutics is of great importance. In the present study, we measured the level of NEDD4L, an ubiquitin protein ligase, in clinical samples and investigated the effects of NEDD4L on cell viability, cell cycle progression, and glutamine metabolism in TE14 cells determined by CCK-8 assay, flow cytometry and biochemical analysis, respectively. The results show that NEDD4L is significantly decreased in ESCC specimens, and its decreased expression is associated with a poor clinical outcome. Overexpression of NEDD4L significantly inhibits cell viability, cell cycle progression, and glutamine metabolism in TE14 cells. Mechanistic study indicates that NEDD4L regulates tumor progression through ubiquitination of c-Myc and modulation of glutamine metabolism. NEDD4L inhibits cell viability, cell cycle progression, and glutamine metabolism in ESCC by ubiquitination of c-Myc to decrease the expressions of GLS1 and SLC1A5. Our findings highlight the importance of NEDD4L/c-Myc signaling in ESCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Genes myc , Proteínas Proto-Oncogénicas c-myc , Humanos , Sistema de Transporte de Aminoácidos ASC/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Glutamina/metabolismo , Antígenos de Histocompatibilidad Menor/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Genes myc/genéticaRESUMEN
B lymphocyte is an important component of the human immune system and it has a role in the process of the body's specific immunity. In recent years, the research on B cells and tumor immune escape has rapidly progressed. Studies have shown that different types of B cells play different roles in tumor microenvironment through a variety of mechanisms. B cells in the tertiary lymphatic structure promote anti-tumor immunity, while regulatory B cells promote tumor immune escape. Antibody drugs targeting B cells are a promising direction for tumor immunotherapy.
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Neoplasias , Escape del Tumor , Linfocitos B/patología , Humanos , Inmunoterapia , Neoplasias/patología , Neoplasias/terapia , Microambiente TumoralRESUMEN
BACKGROUND: Circular RNAs (circRNAs) are widely expressed in human cells and are closely associated with cancer development. However, they have rarely been investigated in the context of nasopharyngeal carcinoma (NPC). METHODS: We screened a new circRNA, circRNF13, in NPC cells using next-generation sequencing of mRNA. Reverse transcription polymerase chain reaction and RNA fluorescence in situ hybridization were used to detect circRNF13 expression in 12 non-tumor nasopharyngeal epithelial (NPE) tissues and 36 NPC samples. Cell proliferation was detected using MTT and flow cytometry assays, and colony formation capability was detected using colony formation assays. Cell migration and invasion were analyzed using wound-healing and Transwell assays, respectively. Cell glycolysis was analyzed using the Seahorse glycolytic stress test. Glucose transporter type 1 (GLUT1) ubiquitination and SUMOylation modifications were analyzed using co-immunoprecipitation and western blotting. CircRNF13 and Small Ubiquitin-like Modifier 2 (SUMO2) interactions were analyzed using RNA pull-down and luciferase reporter assays. Finally, to test whether circRNF13 inhibited NPC proliferation and metastasis in vivo, we used a xenograft nude mouse model generated by means of subcutaneous or tail vein injection. RESULTS: We found that circRNF13 was stably expressed at low levels in NPC clinical tissues and NPC cells. In vitro and in vivo experiments showed that circRNF13 inhibited NPC proliferation and metastasis. Moreover, circRNF13 activated the SUMO2 protein by binding to the 3'- Untranslated Region (3'-UTR) of the SUMO2 gene and prolonging the half-life of SUMO2 mRNA. Upregulation of SUMO2 promotes GLUT1 degradation through SUMOylation and ubiquitination of GLUT1, which regulates the AMPK-mTOR pathway by inhibiting glycolysis, ultimately resulting in the proliferation and metastasis of NPC. CONCLUSIONS: Our results revealed that a novel circRNF13 plays an important role in the development of NPC through the circRNF13-SUMO2-GLUT1 axis. This study implies that circRNF13 mediates glycolysis in NPC by binding to SUMO2 and provides an important theoretical basis for further elucidating the pathogenesis of NPC and targeted therapy.
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Carcinoma Nasofaríngeo/genética , ARN Circular/genética , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Ubiquitina-Proteína Ligasas/genética , Regiones no Traducidas 3' , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Reporteros , Transportador de Glucosa de Tipo 1/metabolismo , Glucólisis , Humanos , Hibridación Fluorescente in Situ , Ratones , Modelos Biológicos , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Invasividad Neoplásica , Metástasis de la Neoplasia , Interferencia de ARN , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Ubiquitinación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Vasculogenic mimicry (VM) is a recently discovered angiogenetic process found in many malignant tumors, and is different from the traditional angiogenetic process involving vascular endothelium. It involves the formation of microvascular channels composed of tumor cells; therefore, VM is considered a new model for the formation of new blood vessels in aggressive tumors, and can provide blood supply for tumor growth. Many studies have pointed out that in recent years, some clinical treatments against angiogenesis have not been satisfactory possibly due to the activation of VM. Although the mechanisms underlying VM have not been fully elucidated, increasing research on the soil "microenvironment" for tumor growth suggests that the initial hypoxic environment in solid tumors is inseparable from VM. MAIN BODY: In this review, we describe that the stemness and differentiation potential of cancer stem cells are enhanced under hypoxic microenvironments, through hypoxia-induced epithelial-endothelial transition (EET) and extracellular matrix (ECM) remodeling to form the specific mechanism of vasculogenic mimicry; we also summarized some of the current drugs targeting VM through these processes, suggesting a new reference for the clinical treatment of tumor angiogenesis. CONCLUSION: Overall, the use of VM inhibitors in combination with conventional anti-angiogenesis treatments is a promising strategy for improving the effectiveness of targeted angiogenesis treatments; further, considering the importance of hypoxia in tumor invasion and metastasis, drugs targeting the hypoxia signaling pathway seem to achieve good results.
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Imitación Molecular , Neoplasias/irrigación sanguínea , Neoplasias/patología , Neovascularización Patológica/patología , Hipoxia Tumoral , Microambiente Tumoral , Animales , Humanos , Células Madre Neoplásicas/patologíaRESUMEN
BACKGROUND: Eukaryotic protein translation elongation factor 1α2 (EEF1A2) is an oncogene that promotes the progression of breast and pancreatic cancer. In this study, we aimed to elucidate the oncogenic function of EEF1A2 in the metastasis of lung adenocarcinoma (LUAD). METHODS: Immunohistochemistry and western blot were used to study EEF1A2 expression levels in LUAD tissues and cells, respectively. The role of EEF1A2 in LUAD progression were investigated in vitro and in vivo. We identified potential EEF1A2-binding proteins by liquid chromatography-electrospray mass spectrometry (LC-MS)/MS. Protein-protein interactions were determined by immunofluorescence and co-immunoprecipitation (Co-IP). RESULTS: In this study, we report that EEF1A2 mediates the epithelial-mesenchymal transformation (EMT), to promote the metastasis of LUAD cells in vitro and in vivo. Moreover, EEF1A2 interacts with HSP90AB1 to increase TGFß Receptor (TßR)-I, and TßRII expression, followed by enhanced SMAD3 and pSMAD3 expression and nuclear localisation, which promotes the EMT of LUAD cells. Overexpression of EEF1A2 in cancer tissues is associated with poor prognosis and short survival of patients with LUAD. CONCLUSIONS: These findings underscore the molecular functions of EEF1A2 in LUAD metastasis and indicate that EEF1A2 represents a promising target in the treatment of aggressive LUAD.
Asunto(s)
Adenocarcinoma del Pulmón/secundario , Regulación Neoplásica de la Expresión Génica , Proteínas HSP90 de Choque Térmico/metabolismo , Neoplasias Pulmonares/patología , Factor 1 de Elongación Peptídica/metabolismo , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Femenino , Proteínas HSP90 de Choque Térmico/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Factor 1 de Elongación Peptídica/genética , Pronóstico , Proteína smad3/genética , Tasa de Supervivencia , Factor de Crecimiento Transformador beta1/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Biological macromolecule condensates formed by liquid-liquid phase separation (LLPS) have been discovered in recent years to be prevalent in biology. These condensates are involved in diverse processes, including the regulation of gene expression. LLPS of proteins have been found in animal, plant, and bacterial species but have scarcely been identified in viral proteins. Here, we discovered that Epstein-Barr virus (EBV) EBNA2 and EBNALP form nuclear puncta that exhibit properties of liquid-like condensates (or droplets), which are enriched in superenhancers of MYC and Runx3. EBNA2 and EBNALP are transcription factors, and the expression of their target genes is suppressed by chemicals that perturb LLPS. Intrinsically disordered regions (IDRs) of EBNA2 and EBNALP can form phase-separated droplets, and specific proline residues of EBNA2 and EBNALP contribute to droplet formation. These findings offer a foundation for understanding the mechanism by which LLPS, previously determined to be related to the organization of P bodies, membraneless organelles, nucleolus homeostasis, and cell signaling, plays a key role in EBV-host interactions and is involved in regulating host gene expression. This work suggests a novel anti-EBV strategy where developing appropriate drugs of interfering LLPS can be used to destroy the function of the EBV's transcription factors.IMPORTANCE Protein condensates can be assembled via liquid-liquid phase separation (LLPS), a process involving the concentration of molecules in a confined liquid-like compartment. LLPS allows for the compartmentalization and sequestration of materials and can be harnessed as a sensitive strategy for responding to small changes in the environment. This study identified the Epstein-Barr virus (EBV) proteins EBNA2 and EBNALP, which mediate virus and cellular gene transcription, as transcription factors that can form liquid-like condensates at superenhancer sites of MYC and Runx3. This study discovered the first identified LLPS of EBV proteins and emphasized the importance of LLPS in controlling host gene expression.
Asunto(s)
Antígenos Nucleares del Virus de Epstein-Barr/química , Regulación de la Expresión Génica , Proteínas Intrínsecamente Desordenadas/química , Proteínas Virales/química , Línea Celular Tumoral , Nucléolo Celular/química , Núcleo Celular , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Genes myc , Células HEK293 , Herpesvirus Humano 4/fisiología , Humanos , Leucocitos Mononucleares , Microscopía Fluorescente , Prolina/química , Regiones Promotoras Genéticas , Dominios ProteicosRESUMEN
Epstein-Barr virus (EBV) infection leads to cancers with an epithelial origin, such as nasopharyngeal cancer and gastric cancer, as well as multiple blood cell-based malignant tumors, such as lymphoma. Interestingly, EBV is also the first virus found to carry genes encoding miRNAs. EBV encodes 25 types of pre-miRNAs which are finally processed into 44 mature miRNAs. Most EBV-encoded miRNAs were found to be involved in the occurrence and development of EBV-related tumors. However, the function of EBV-miR-BART12 remains unclear. The findings of the current study revealed that EBV-miR-BART12 binds to the 3'UTR region of Tubulin Polymerization-Promoting Protein 1 (TPPP1) mRNA and downregulates TPPP1, thereby promoting the invasion and migration of EBV-related cancers, such as nasopharyngeal cancer and gastric cancer. The mechanism underlying this process was found to be the inhibition of TPPP1 by EBV-miRNA-BART12, which, in turn, inhibits the acetylation of α-tubulin, and promotes the dynamic assembly of microtubules, remodels the cytoskeleton, and enhances the acetylation of ß-catenin. ß-catenin activates epithelial to mesenchymal transition (EMT). These two processes synergistically promote the invasion and metastasis of tumor cells. To the best of our knowledge, this is the first study to reveal the role of EBV-miRNA-BART12 in the development of EBV-related tumors as well as the mechanism underlying this process, and suggests potential targets and strategies for the treatment of EBV-related tumors.
Asunto(s)
Movimiento Celular/genética , Proteínas del Citoesqueleto/genética , Herpesvirus Humano 4/genética , MicroARNs/genética , Carcinoma Nasofaríngeo/virología , Neoplasias Gástricas/virología , Factores de Transcripción/genética , Regiones no Traducidas 3'/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación hacia Abajo/genética , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/virología , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Carcinoma Nasofaríngeo/genética , Polimerizacion , ARN Viral/genética , Neoplasias Gástricas/genética , beta Catenina/genéticaRESUMEN
Epstein-Barr virus (EBV) is a tumorigenic virus that can cause various human malignancies such as nasopharyngeal carcinoma (NPC) and gastric cancer (GC). EBV encodes 44 mature micro (mi)RNAs, mostly exhibiting oncogenic properties and promoting cancer progression. However, we have previously found that one EBV-encoded miRNA, namely EBV-miR-BART6-3p, acts as a tumor suppressor by inhibiting metastasis and invasion. Here, we report that EBV-miR-BART6-3p inhibits the proliferation of EBV-associated cancers, NPC, and GC, by targeting and downregulating a long non-coding RNA (lncRNA), LOC553103. Through proteomics analysis, we determined that stathmin (STMN1) is affected by EBV-miR-BART6-3p and LOC553103. Further, via RNA immunoprecipitation and luciferase reporter assay, we confirmed that LOC553103 directly binds and stabilizes the 3'UTR region of STMN1 mRNA. These results indicate that the EBV-miR-BART6-3p/LOC553103/STMN1 axis regulates the expression of cell cycle-associated proteins, which then inhibit EBV-associated tumor cell proliferation. These findings provide potential targets or strategies for novel EBV-related cancer treatments, as well as contributes new insights into the understanding of EBV infection-related carcinogenesis.