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BACKGROUND: Glioblastoma multiforme (GBM) is identified as one of the most prevalent and malignant brain tumors, characterized by poor treatment outcomes and a limited prognosis. CMTM6, a membrane protein, has been found to upregulate the expression of programmed cell death 1 ligand 1 protein (PD-L1) and acts as an immune checkpoint inhibitor by inhibiting the programmed death 1 protein/PD-L1 signaling pathway. Recent research has demonstrated a high expression of CMTM6 in GBM, suggesting its potential role in influencing the pathogenesis and progression of GBM, as well as its association with immune cell infiltration in the tumor microenvironment. However, the underlying mechanism of CMTM6 in GBM requires further investigation. METHODS: Data from cancer patients in The Cancer Genome Atlas, Gene Expression Omnibus and Chinese Glioma Genome Atlas cohorts were consolidated for the current study. Through multi-omics analysis, the study systematically examined the expression profile of CMTM6, epigenetic modifications, prognostic significance, biological functions, potential mechanisms of action and alterations in the immune microenvironment. Additionally, the study investigated CMTM6 expression in GBM cell lines and normal cells using reverse transcription PCR and western blot analysis. The impact of CMTM6 on GBM cell proliferation, migration and invasion was evaluated using a combination of cell counting kit-8 assay, clone formation assay, 5-ethynyl-2'-deoxyuridine incorporation assay, wound healing assay and Transwell assay. In order to explore the mechanism of CMTM6, the Wnt/ß-catenin signaling pathway and autophagy-related genes were further verified through western blot analysis. RESULTS: CMTM6 is highly expressed in multiple tumors, particularly GBM. CMTM6 has been shown to be a valuable diagnostic and prognostic biomarker by various bioinformatics approaches. Additionally, CMTM6 plays a pivotal role in the pathogenesis of cancer, specifically GBM, by modulating various biological processes such as DNA methyltransferase expression, RNA modification, copy number variation, genomic heterogeneity, tumor stemness and DNA methylation. The findings of the experiment indicate a significant correlation between elevated CMTM6 expression and the proliferation, invasion, migration and autophagy of GBM cells, with potential key roles mediated through the Wnt/ß-catenin signaling pathway. Furthermore, CMTM6 is implicated in modulating tumor immune cell infiltration and is closely linked to the expression of various immune checkpoint inhibitors and immune modulators, particularly within the context of GBM. High levels of CMTM6 expression also enhance the responsiveness of GBM patients to radiotherapy and chemotherapy, thereby offering valuable insights for guiding treatment strategies for GBM. CONCLUSIONS: Autophagy-related CMTM6 is highly expressed in various types of cancer, especially GBM, and it can regulate GBM progression through the Wnt/ß-catenin signaling pathway and is capable of being used as an underlying target for the diagnosis, treatment selection and prognosis of patients with GBM.
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Autofagia , Biomarcadores de Tumor , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Glioblastoma , Proteínas con Dominio MARVEL , Microambiente Tumoral , Vía de Señalización Wnt , Humanos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Proteínas con Dominio MARVEL/metabolismo , Proteínas con Dominio MARVEL/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Microambiente Tumoral/inmunología , Línea Celular Tumoral , Autofagia/genética , Pronóstico , Proliferación Celular , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proteínas de la Mielina/genética , Proteínas de la Mielina/metabolismo , Movimiento Celular/genética , beta Catenina/metabolismo , beta Catenina/genéticaRESUMEN
Due to its tumor homing and long serum half-life, albumin is an ideal drug carrier for chemotherapy. For endogenous albumin hitchhiking with high cargo loading, a trimeric albumin-binding domain (ABD), i.e., ABD-Tri is designed by fusing an ABD with high specificity and affinity for albumin to a self-trimerizing domain (Tri) with an additional cysteine residue. ABD-Tri is highly (40 mg L-1) expressed as soluble and trimeric proteins in Escherichia coli (E. coli). Once mixed together, ABD-Tri rapidly and specifically forms a stable complex with albumin under physiological conditions without obviously changing its receptor- and cell-binding and tumor-homing properties. Maleimide-modified prodrugs are highly effectively conjugated to ABD-Tri to produce homogenous ABD-Tri-prodrugs with triple cargo loading under physiological conditions by thiol-maleimide click chemistry. Unlike the maleimide moiety, which can only mediate time- and concentration-dependent albumin binding, ABD-Tri mediated fast (within several minutes) albumin binding of drugs even at extremely low concentrations (µg mL-1). Compared to maleimide-modified prodrugs, ABD-Tri-prodrugs exhibit better tumor homing and greater in vivo antitumor effect, indicating that conjugation of chemical drug to ABD-Tri outperforms maleimide modification for endogenous albumin hitchhiking. The results demonstrate that ABD-Tri may serve as a novel platform to produce albumin-binding prodrugs with high cargo-loading capacity for tumor-targeted chemotherapy.
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Neoplasias , Profármacos , Compuestos de Sulfhidrilo , Humanos , Profármacos/química , Albúmina Sérica , Escherichia coli/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Maleimidas/químicaRESUMEN
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne viral disease caused by the SFTS virus (Dabie bandavirus), which has become a substantial risk to public health. No specific treatment is available now, that calls for an effective vaccine. Given this, we aimed to develop a multi-epitope DNA vaccine through the help of bioinformatics. The final DNA vaccine was inserted into a special plasmid vector pVAX1, consisting of CD8+ T cell epitopes, CD4+ T cell epitopes and B cell epitopes (six epitopes each) screened from four genome-encoded proteins--nuclear protein (NP), glycoprotein (GP), RNA-dependent RNA polymerase (RdRp), as well as nonstructural protein (NSs). To ascertain if the predicted structure would be stable and successful in preventing infection, an immunological simulation was run on it. In conclusion, we designed a multi-epitope DNA vaccine that is expected to be effective against Dabie bandavirus, but in vivo trials are needed to verify this claim.
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Epítopos de Linfocito T , Phlebovirus , Síndrome de Trombocitopenia Febril Grave , Vacunas de ADN , Vacunas Virales , Vacunas de ADN/inmunología , Vacunas de ADN/genética , Phlebovirus/inmunología , Phlebovirus/genética , Síndrome de Trombocitopenia Febril Grave/prevención & control , Síndrome de Trombocitopenia Febril Grave/inmunología , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/genética , Vacunas Virales/inmunología , Vacunas Virales/genética , Humanos , Diseño Asistido por Computadora , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito B/genética , Animales , Biología ComputacionalRESUMEN
Suppressor of cytokine signalling (SOCS) 1/2/3/4 are involved in the occurrence and progression of multiple malignancies; however, their prognostic and developmental value in patients with glioblastoma (GBM) remains unclear. The present study used TCGA, ONCOMINE, SangerBox3.0, UALCAN, TIMER2.0, GENEMANIA, TISDB, The Human Protein Atlas (HPA) and other databases to analyse the expression profile, clinical value and prognosis of SOCS1/2/3/4 in GBM, and to explore the potential development mechanism of action of SOCS1/2/3/4 in GBM. The majority of analyses showed that SOCS1/2/3/4 transcription and translation levels in GBM tissues were significantly higher than those in normal tissues. qRT-PCR, western blotting (WB) and immunohistochemical staining were used to verify that SOCS3 was expressed at higher mRNA and protein levels in GBM than in normal tissues or cells. High SOCS1/2/3/4 mRNA expression was associated with poor prognosis in patients with GBM, especially SOCS3. SOCS1/2/3/4 were highly contraindicated, which had few mutations, and were not associated with clinical prognosis. Furthermore, SOCS1/2/3/4 were associated with the infiltration of specific immune cell types. In addition, SOCS3 may affect the prognosis of patients with GBM through JAK/STAT signalling pathway. Analysis of the GBM-specific protein interaction (PPI) network showed that SOCS1/2/3/4 were involved in multiple potential carcinogenic mechanisms of GBM. In addition, colony formation, Transwell, wound healing and western blotting assays revealed that inhibition of SOCS3 decreased the proliferation, migration and invasion of GBM cells. In conclusion, the present study elucidated the expression profile and prognostic value of SOCS1/2/3/4 in GBM, which may provide potential prognostic biomarkers and therapeutic targets for GBM, especially SOCS3.
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Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/patología , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas , Pronóstico , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , ARN Mensajero/metabolismo , BiomarcadoresRESUMEN
CD25 is the alpha-chain of the heterotrimer IL-2 receptor. CD25 is expressed on the surface of both immune and non-immune cells with different frequencies. For cancers, CD25 is expressed at high levels in many types of hematological malignancies, but at low levels in most solid tumors. CD25 is also highly expressed in activated circulating immune cells and regulatory T cells (Tregs). Infiltration of Tregs in the tumor microenvironment can lead to an imbalanced ratio of effector T cells (Teffs) and Tregs, which is associated with the progression of cancers. A rescued Teff/Treg cell ratio indicates an efficient anti-tumor response to immunotherapy. CD25 as a potential target for the depletion of Tregs is critical in developing new immunotherapeutic strategies. Few articles have summarized the relationships between CD25 and tumors, or the recent progress of drugs targeting CD25. In this paper, we will discuss the structures of IL-2 and IL-2R, the biological function of CD25 and its important role in tumor therapy. In addition, the latest research on drugs targeting CD25 has been summarized, providing guidance for future drug development.
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Neoplasias , Linfocitos T Reguladores , Humanos , Subunidad alfa del Receptor de Interleucina-2 , Neoplasias/tratamiento farmacológico , Inmunoterapia , Microambiente TumoralRESUMEN
BACKGROUND: Metastatic prostate cancer (mPCa) has a poor prognosis with limited treatment options. The high mobility of tumor cells is the key driving characteristic of metastasis. However, the mechanism is complex and far from clarified in PCa. Therefore, it is essential to explore the mechanism of metastasis and discover an intrinsic biomarker for mPCa. METHODS: Transcriptome sequencing data and clinicopathologic features of PCa from multifarious public databases were used to identify novel metastatic genes in PCa. The PCa tissue cohort containing 102 formalin-fixed paraffin-embedded (FFPE) samples was used to evaluate the clinicopathologic features of synaptotagmin-like 2 (SYTL2) in PCa. The function of SYTL2 was investigated by migration and invasion assays and a 3D migration model in vitro and a popliteal lymph node metastasis model in vivo. We performed coimmunoprecipitation and protein stability assays to clarify the mechanism of SYTL2. RESULTS: We discovered a pseudopodia regulator, SYTL2, which correlated with a higher Gleason score, worse prognosis and higher risk of metastasis. Functional experiments revealed that SYTL2 promoted migration, invasion and lymph node metastasis by increasing pseudopodia formation in vitro and in vivo. Furthermore, SYTL2 induced pseudopodia formation by enhancing the stability of fascin actin-bundling protein 1 (FSCN1) by binding and inhibiting the proteasome degradation pathway. Targeting FSCN1 enabled rescue and reversal of the oncogenic effect of SYTL2. CONCLUSIONS: Overall, our study established an FSCN1-dependent mechanism by which SYTL2 regulates the mobility of PCa cells. We also found that the SYTL2-FSCN1-pseudopodia axis may serve as a pharmacological and novel target for treating mPCa.
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Proteínas Portadoras , MicroARNs , Proteínas de Microfilamentos , Neoplasias de la Próstata , Humanos , Masculino , Proteínas Portadoras/genética , Línea Celular Tumoral , Movimiento Celular/genética , Metástasis Linfática , Proteínas de Microfilamentos/genética , MicroARNs/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Seudópodos/metabolismo , Proteínas de la Membrana/genéticaRESUMEN
BACKGROUND: CD276 (also known as B7-H3) is one of the most important immune checkpoints of the CD28 and B7 superfamily, and its abnormal expression is closely associated with various types of cancer. It has been shown that CD276 is able to inhibit the function of T cells, and that this gene may potentially be a promising immunotherapy target for different types of cancer. METHODS: Since few systematic studies have been published on the role of CD276 in cancer to date, the present study has employed single-cell sequencing and bioinformatics methods to analyze the expression patterns, clinical significance, prognostic value, epigenetic alterations, DNA methylation level, tumor immune cell infiltration and immune functions of CD276 in different types of cancer. In order to analyze the potential underlying mechanism of CD276 in glioblastoma (GBM) to assess its prognostic value, the LinkedOmics database was used to explore the biological function and co-expression pattern of CD276 in GBM, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. In addition, a simple validation of the above analyses was performed using reverse transcription-quantitative (RT-q)PCR assay. RESULTS: The results revealed that CD276 was highly expressed, and was often associated with poorer survival and prognosis, in the majority of different types of cancer. In addition, CD276 expression was found to be closely associated with T cell infiltration, immune checkpoint genes and immunoregulatory interactions between lymphoid and a non-lymphoid cell. It was also shown that the CD276 expression network exerts a wide influence on the immune activation of GBM. The expression of CD276 was found to be positively correlated with neutrophil-mediated immunity, although it was negatively correlated with the level of neurotransmitters, neurotransmitter transport and the regulation of neuropeptide signaling pathways in GBM. It is noteworthy that CD276 expression was found to be significantly higher in GBM compared with normal controls according to the RT-qPCR analysis, and the co-expression network, biological function and chemotherapeutic drug sensitivity of CD276 in GBM were further explored. In conclusion, the findings of the present study have revealed that CD276 is strongly expressed and associated with poor prognosis in most types of cancer, including GBM, and its expression is strongly associated with T-cell infiltration, immune checkpoint genes, and immunomodulatory interactions between lymphocytes and non-lymphoid cells. CONCLUSIONS: Taken together, based on our systematic analysis, our findings have revealed important roles for CD276 in different types of cancers, especially GBM, and CD276 may potentially serve as a biomarker for cancer.
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Glioblastoma , Humanos , Glioblastoma/genética , Pronóstico , Multiómica , Genes Reguladores , Factores de Transcripción , Antígenos B7/genéticaRESUMEN
Tacrolimus (TAC) and sirolimus (SIR) antirejection medications are widely used in organ transplantation. We aimed to develop an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) assay for quantifying TAC and SIR simultaneously and evaluating agreement with chemiluminescence microparticle immunoassay (CMIA) and electrochemiluminescence immunoassay (ECLIA). Whole blood samples collected from 209 TAC and 208 SIR patients were assessed by UHPLC-MS/MS, CMIA and ECLIA. The agreement of the three techniques was assessed using the Bland-Altman plot. The UHPLC-MS/MS assay had a calibration range of 1-100 ng/ml for TAC and SIR. The accuracy and precision were -2.73-4.32% and <4.71% for TAC, respectively, and 0.07-4.84% and <6.5% for SIR, respectively. The three methods had good correlation. In comparison with UHPLC-MS/MS, two immunoassays showed a slight deviation in proportion. An UHPLC-MS/MS method for simultaneously detecting TAC and SIR in human whole blood was developed, validated and comparatively analyzed with CMIA and ECLIA. For determining TAC and SIR, immunoassays displayed acceptable analytical performances in terms of precision and correlation compared with UHPLC-MS/MS. However, further investigation is warranted to examine the novel method.
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Sirolimus , Tacrolimus , Humanos , Cromatografía Líquida de Alta Presión/métodos , Inmunosupresores , Espectrometría de Masas en Tándem/métodos , Monitoreo de Drogas/métodos , Inmunoensayo/métodosRESUMEN
Microtubules composed of α/ß tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure-activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.
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Quinasa de la Caseína I/antagonistas & inhibidores , Diseño de Fármacos , Indoles/química , Microtúbulos/efectos de los fármacos , Floroglucinol/análogos & derivados , Tubulina (Proteína)/química , Animales , Sitios de Unión , Colchicina/química , Colchicina/metabolismo , Cristalografía por Rayos X , Indoles/metabolismo , Simulación del Acoplamiento Molecular , Floroglucinol/química , Floroglucinol/metabolismo , Conformación Proteica , Relación Estructura-Actividad , Porcinos , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismoRESUMEN
The discovery of novel non-invasive biomarkers for discriminating between prostate carcinoma (PCa) patients and benign prostatic hyperplasia (BPH) patients is necessary to reduce the burden of biopsies, avoid overdiagnosis and improve quality of life. Previous studies suggest that abnormal glycosylation of immunoglobulin gamma molecules (IgGs) is strongly associated with immunological diseases and prostate diseases. Hence, characterizing N-linked intact glycopeptides of IgGs that correspond to the N-glycan structure with specific site information might enable a better understanding of the molecular pathogenesis and discovery of novel signatures in preoperative discrimination of BPH from PCa. In this study, we profiled N-linked intact glycopeptides of purified IgGs from 51 PCa patients and 45 BPH patients by our developed N-glycoproteomic method using hydrophilic interaction liquid chromatography enrichment coupled with high resolution LC-MS/MS. The quantitative analysis of the N-linked intact glycopeptides using pGlyco 2.0 and MaxQuant software provided quantitative information on plasma IgG subclass-specific and site-specific N-glycosylation. As a result, we found four aberrantly expressed N-linked intact glycopeptides across different IgG subclasses. In particular, the N-glycopeptide IgG2-GP09 (EEQFNSTFR (H5N5S1)) was dramatically elevated in plasma from PCa patients, compared with that in BPH patients (PCa/BPH ratio = 5.74, p = 0.001). Additionally, the variations in these N-linked intact glycopeptide abundances were not caused by the changes in the IgG concentrations. Furthermore, IgG2-GP09 displayed a more powerful prediction capability (auROC = 0.702) for distinguishing PCa from BPH than the clinical index t-PSA (auROC = 0.681) when used alone or in combination with other indicators (auROC = 0.853). In conclusion, these abnormally expressed N-linked intact glycopeptides have potential for non-invasive monitoring and pre-stratification of prostate diseases.
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Carcinoma , Hiperplasia Prostática , Neoplasias de la Próstata , Cromatografía Liquida , Glicopéptidos , Humanos , Masculino , Antígeno Prostático Específico , Hiperplasia Prostática/diagnóstico , Neoplasias de la Próstata/diagnóstico , Calidad de Vida , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: Glioma is the most commonly diagnosed malignant and aggressive brain cancer in adults. Traditional researches mainly explored the expression profile of glioma at cell-population level, but ignored the heterogeneity and interactions of among glioma cells. METHODS: Here, we firstly analyzed the single-cell RNA-seq (scRNA-seq) data of 6341 glioma cells using manifold learning and identified neoplastic and healthy cells infiltrating in tumor microenvironment. We systematically revealed cell-to-cell interactions inside gliomas based on corresponding scRNA-seq and TCGA RNA-seq data. RESULTS: A total of 16 significantly correlated autocrine ligand-receptor signal pairs inside neoplastic cells were identified based on the scRNA-seq and TCGA data of glioma. Furthermore, we explored the intercellular communications between cancer stem-like cells (CSCs) and macrophages, and identified 66 ligand-receptor pairs, some of which could significantly affect prognostic outcomes. An efficient machine learning model was constructed to accurately predict the prognosis of glioma patients based on the ligand-receptor interactions. CONCLUSION: Collectively, our study not only reveals functionally important cell-to-cell interactions inside glioma, but also detects potentially prognostic markers for predicting the survival of glioma patients.
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Comunicación Autocrina , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Transcriptoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glioma/genética , Glioma/patología , Humanos , Aprendizaje Automático , Células Madre Neoplásicas/metabolismoRESUMEN
5T4, a membrane protein, is overexpressed in many tumor tissues but rarely expressed in normal tissues. Here, CHO-5T4+ cells were generated and served as the antigen to immunize mice. Hybridoma techniques were employed to produce monoclonal antibodies (mAbs). The recombinant protein of human IgG Fc-fused extracellular domain of 5T4 (5T4 ECD-Fc) was obtained from transient expression in HEK293F cells. The fusion protein 5T4 ECD-Fc and CHO-5T4+ cells were respectively utilized to screen anti-5T4 antibodies that could bind to the native antigen. In preliminary screening, three hundred and fifty mAbs were obtained. Via surface plasmon resonance and flow cytometry screening, seven anti-5T4 mAbs stood out. Among them, H6 showed a high affinity (KDâ¯=â¯1.6â¯×â¯10-11â¯M) and internalization percentage (36% for 1â¯h and 80% for 4â¯h). The molecular weight and isoelectric point of H6 were determined by LC-MS and iCIEF. Moreover, the specific reactivity of H6 was demonstrated by western blotting, flow cytometry, and immunohistochemistry, respectively. In conclusion, we produced human recombinant protein of 5T4 extracellular domain and developed high-affinity internalizing monoclonal antibodies which may be applied in the 5T4-targeting ADC therapy and basic research.
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Anticuerpos Monoclonales de Origen Murino , Afinidad de Anticuerpos , Antineoplásicos Inmunológicos , Fragmentos Fc de Inmunoglobulinas , Glicoproteínas de Membrana , Proteínas Recombinantes de Fusión , Animales , Anticuerpos Monoclonales de Origen Murino/química , Anticuerpos Monoclonales de Origen Murino/inmunología , Antineoplásicos Inmunológicos/química , Antineoplásicos Inmunológicos/inmunología , Células CHO , Cricetulus , Femenino , Humanos , Fragmentos Fc de Inmunoglobulinas/biosíntesis , Fragmentos Fc de Inmunoglobulinas/química , Fragmentos Fc de Inmunoglobulinas/inmunología , Fragmentos Fc de Inmunoglobulinas/aislamiento & purificación , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/aislamiento & purificación , Ratones , Ratones Endogámicos BALB C , Dominios Proteicos , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/aislamiento & purificaciónRESUMEN
OBJECTIVES: Prostate cancer (PRAD) is a highly malignant disease with poor prognosis, and its development is regulated by a complex network of genes and signaling pathways. LncRNAs and miRNAs have significant regulatory roles in PRAD through the ceRNA network. Cuproptosis is a unique form of programmed cell death that is involved in various signaling pathways and biological processes related to tumor development. Nuclear factor of activated T cells 5 (NFAT5), a transcription factor that activates T cells, has been implicated in cuproptosis. However, the regulatory mechanism by which NFAT5 is involved in the ceRNA network in PRAD remains unclear. METHODS: Through bioinformatics analysis, we found the ceRNA axis that regulates cuproptosis. By performing ROS assay and copper ion concentration assay, we demonstrated that inhibiting NFAT5 can increase the sensitivity of PRAD to cuproptosis inducers. By using luciferase assay, we discovered that AP000842.3 acts as the ceRNA of miR-206 to regulate the expression of NFAT5. RESULTS: In this study, we found that lncRNA AP000842.3, as a ceRNA of miR-206, was involved in the regulation of levels of the transcription factor NFAT5 associated with cuproptosis in PRAD. First, knocking down NFAT5 can increase the sensitivity of PRAD to cuproptosis inducers. Meanwhile, changes in the expression of AP000842.3 and miR-206 could affect the proliferation of PRAD by regulating NFAT5. Mechanistically, AP000842.3 acts as the ceRNA of miR-206 to regulate the expression of NFAT5. In addition, the effects of lncRNA AP000842.3 on malignant progression of PRAD and NFAT5 were partially dependent on miR-206. CONCLUSION: Taken together, our study reveals a key ceRNA regulatory network in PRAD and can be regarded as a new potential target for PRAD diagnosis and treatment.
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Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , MicroARNs , Neoplasias de la Próstata , ARN Largo no Codificante , Factores de Transcripción , Humanos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , ARN Largo no Codificante/genética , Masculino , MicroARNs/genética , Línea Celular Tumoral , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ratones , Proliferación Celular , Animales , Biología Computacional/métodos , Redes Reguladoras de GenesRESUMEN
Background: Radiologists currently accept the concept of "interfascial plane (IFP)" to understand retroperitoneal anatomy, replacing Meyers' classic tricompartmental theory. Despite much research on retroperitoneal anatomy, its anatomical structure, embryonic origin and developmental process still require further exploration to guide the optimization of surgical process. This study aims to explore the anatomical basis of IFP related to laparoscopic upper retroperitoneal surgery (LURS) and to compare the clinical outcomes of trans-interfascial plane procedures for LURS (TIFP-LURS) with conventional LURS (Con-LURS). Methods: The study consisted of two parts: cadaveric and clinical study. The cadaveric study involved dissecting and observing the retroperitoneal fasciae and IFP in 32 cadavers using gross anatomical and histological methods. This retrospective clinical study compared the perioperative data and complications of 229 patients who underwent TIFP-LURS and 121 patients who underwent Con-LURS for upper retroperitoneal lesions at our center. Results: The cadaveric study revealed that the retroperitoneal space was composed of multilaminar fasciae that formed potential bloodless spaces among them, that could be used as surgical landmarks and operating planes. The clinical study showed that TIFP-LURS had a significantly less estimated blood loss, lower intraoperative complication rate, lower postoperative complication rate, shorter hospital-stay and lower long-term postoperative complications rate than Con-LURS. Multivariate analysis indicated that the TIFP procedure was an independent protective factor for decreasing the risk of postoperative complications. Conclusions: The IFP are potential avascular spaces that can be used during laparoscopic surgery, and TIFP-LURS is a novel surgical approach that can improve the safety and efficacy of laparoscopic surgery for upper retroperitoneal lesions.
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Antibody-drug conjugates (ADCs) have emerged as a novel class of targeted cancer therapies and been successfully applied in the treatment of breast cancer (BC). Discoidin domain receptor 1 (DDR1) is a single transmembrane receptor tyrosine kinase and has been identified as a possible target for cancer. In this study, we explored the potential of an anti-DDR1 ADC, named T4H11-DM4, for the treatment of DDR1-positive BC. We demonstrated that high protein expression and RNA expression of DDR1 in BC tissues. In vitro, T4H11-DM4 was potently cytotoxic to DDR1-expressing BC cells, with IC50 in the nanomolar range. In mice BC xenograft models, T4H11-DM4 dramatically eliminated BC tumours, without observable toxicity. Taken together, our findings demonstrated that DDR1 can serve as a promising therapeutic target for BC.
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Circular RNAs (circRNAs) are a family of endogenous RNAs that have become a focus of biological research in recent years. Emerging evidence has revealed that circRNAs exert biological functions by acting as transcriptional regulators, microRNA sponges, and binding partners with RNA-binding proteins. However, few studies have identified coding circRNAs, which may lead to a hidden repertoire of proteins. In this study, we unexpectedly discovered a protein-encoding circular RNA circCCDC7(15,16,17,18,19) while we were searching for prostate cancer related chimeric RNAs. circCCDC7(15,16,17,18,19) is derived from exon 19 back spliced to exon 15 of the CCDC7 gene. It is significantly downregulated in patients with high Gleason score. Prostate cancer patients with decreased circCCDC7(15,16,17,18,19) expression have a worse prognosis, while linear CCDC7 had no such association. Overexpressed circCCDC7(15,16,17,18,19) inhibited prostate cancer cell migration, invasion, and viability, supporting classification of circCCDC7(15,16,17,18,19) as a bona fide tumor suppressor gene. We provide evidence that its tumor suppressive activity is driven by the protein it encodes, and that circCCDC7(15,16,17,18,19) encodes a secretory protein. Consistently, conditioned media from circCCDC7(15,16,17,18,19) overexpressing cells has the same tumor suppressive activity. We further demonstrate that the tumor suppressive activity of circCCDC7(15,16,17,18,19) is at least partially mediated by FLRT3, whose expression also negatively correlates with Gleason score and clinical prognosis. In conclusion, circCCDC7(15,16,17,18,19) functions as a tumor suppressor in prostate cancer cells through the circCCDC7-180aa secretory protein it encodes, and is a promising therapeutic peptide for prostate cancer.
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Excess intracellular reactive oxygen species (ROS) beyond a threshold can induce apoptosis in cancer cells. However, the signal pathways that can augment the proapoptotic function of ROS remain largely unknown. We previously identified a tumor suppressor, alpha-tocopherol-associated protein (TAP), yet little is known regarding the role of TAP in the apoptotic signaling in prostate cancer. Interestingly, we recently found that exposure of prostate cancer cells to hydrogen peroxide (H(2)O(2) ) resulted in induced apoptosis as well as increased expression of TAP. Small interfering RNA (siRNA) mediated silencing of endogenous TAP expression conferred effective protection from H(2)O(2) -induced apoptosis. Further mechanistic study showed exposure of prostate cancer cells to H(2)O(2) resulted in increased phosphorylation of both JNK and c-Jun, and TAP siRNA effectively decreased H(2)O(2) -induced JNK and c-Jun phosphorylation. Immunoprecipitation experiments revealed that JNK physically associates with TAP. Furthermore, signaling downstream of JNK to the AP-1 complex and BH-3-only subfamily were found to be regulated on changing the TAP expression status. TAP could also promote the oxidative stress-induced apoptosis effect of docetaxel. In the mice xenograft model, H(2)O(2) treatment induced TAP expression, JNK phosphorylation and apoptosis of prostate cancer. Recombinant adeno-associated virus 2 (rAAV2)-TAP injection significantly sensitizes this H(2)O(2) proapoptotic effect. Together, we have identified a novel functional mechanism that the cross-talk of TAP-JNK is involved in oxidative stress-induced apoptosis in prostate cancer cells. Disrupting the redox balance of cancer cells by this signaling may enable therapeutic selectivity and provide benefit to overcome the drug resistance of prostate cancer.
Asunto(s)
Apoptosis , Proteínas Portadoras/metabolismo , MAP Quinasa Quinasa 4/metabolismo , Estrés Oxidativo , Neoplasias de la Próstata/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptor Cross-Talk , Animales , Western Blotting , Proteínas Portadoras/genética , Activación Enzimática , Silenciador del Gen , Humanos , Peróxido de Hidrógeno/metabolismo , Inmunoprecipitación , Etiquetado Corte-Fin in Situ , Masculino , Ratones , Ratones Desnudos , Reacción en Cadena de la Polimerasa/métodos , Neoplasias de la Próstata/enzimología , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Trasplante HeterólogoRESUMEN
Alzheimer's disease (AD) is the most common cause of memory disruption in elderly subjects, with the prevalence continuing to rise mainly because of the aging world population. Unfortunately, no efficient therapy is currently available for the AD treatment, due to low drug potency and several challenges to delivery, including low bioavailability and the impediments of the blood-brain barrier. Recently, nanomedicine has gained considerable attention among researchers all over the world and shown promising developments in AD treatment. A wide range of nano-carriers, such as polymer nanoparticles, liposomes, solid lipid nanoparticles, dendritic nanoparticles, biomimetic nanoparticles, magnetic nanoparticles, etc., have been adapted to develop successful new treatment strategies. This review comprehensively summarizes the recent advances of different nanomedicine for their efficacy in pre-clinical studies. Finally, some insights and future research directions are proposed. This review can provide useful information to guide the future design and evaluation of nanomedicine in AD treatment.
RESUMEN
The estrogen receptor (ER) is a classical receptor protein that plays a crucial role in mediating multiple signaling pathways in various target organs. It has been shown that ER-targeting therapies inhibit breast cancer cell proliferation, enhance neuronal protection, and promote osteoclast formation. Several drugs have been designed to specifically target ER in ER-positive (ER+) breast cancer, including selective estrogen receptor modulators (SERM) such as Tamoxifen. However, the emergence of drug resistance in ER+ breast cancer and the potential side effects on the endometrium which has high ER expression has posed significant challenges in clinical practice. Recently, novel ER-targeted drugs, namely, selective estrogen receptor degrader (SERD) and selective estrogen receptor covalent antagonist (SERCA) have shown promise in addressing these concerns. This paper provides a comprehensive review of the structural functions of ER and highlights recent advancements in SERD and SERCA-related small molecule drugs, especially focusing on their structural optimization strategies and future optimization directions. Additionally, the therapeutic potential and challenges of novel SERDs and SERCAs in breast cancer and other ER-related diseases have been discussed.
RESUMEN
The "do not eat me" signaling pathway is extremely active in tumor cells, providing a means for these cells to elude macrophage phagocytosis and escape immune surveillance. Representative markers of this pathway, such as CD47 and CD24, are highly expressed in numerous tumors. The interaction of SIRPα with CD47 reduces the accumulation of non-myosin â ¡A on the cell membrane. The combination of CD24 and Siglec10 ultimately leads to the recruitment of SHP-1 or SHP-2 to reduce signal transduction. Both of them weaken the ability of macrophages to engulf tumor cells. Blocking the mutual recognition between CD47-SIRPα or CD24-Siglec10 using large molecular proteins or small molecular drugs represents a promising avenue for tumor immunotherapy. Doing so can inhibit signal transduction and enhance macrophage clearance rates of cancer cells. In this paper, we summarize the characteristics of the drugs that affect the "do not eat me" signaling pathway via classical large molecular proteins and small molecule drugs, which target the CD47-SIRPα and CD24-Siglec10 signaling pathways, which target the CD47-SIRPα and CD24-Siglec10 signaling pathways. We expect it will offer insight into the development of new drugs centered on blocking the "do not eat me" signaling pathway.