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BACKGROUND: Prostate cancer (PCa) has become the highest incidence of malignant tumor among men in the world. Tumor microenvironment (TME) is necessary for tumor growth. M2 macrophages play an important role in many solid tumors. This research aimed at the role of M2 macrophages' prognosis value in PCa. METHODS: Single-cell RNA-seq (scRNA-seq) data and mRNA expression data were obtained from the Gene Expression Omnibus database (GEO) and The Cancer Genome Atlas (TCGA). Quality control, normalization, reduction, clustering, and cell annotation of scRNA-seq data were preformed using the Seruat package. The sub-populations of the tumor-associated macrophages (TAMs) were analysis and the marker genes of M2 macrophage were selected. Differentially expressed genes (DEGs) in PCa were identified using limma and the immune infiltration was detected using CIBERSORTx. Then, a weighted correlation network analysis (WGCNA) was constructed to identify the M2 macrophage-related modules and genes. Integration of the marker genes of M2 macrophage from scRNA-seq data analysis and hub genes from WGCNA to select the prognostic gene signature based on Univariate and LASSO regression analysis. The risk score was calculated, and the DEGs, biological function, immune characteristics related to risk score were explored. And a predictive nomogram was constructed. CCK8, Transwell, and wound healing were used to verify cell phenotype changes after co-cultured. RESULTS: A total of 2431 marker genes of M2 macrophage and 650 hub M2 macrophage-related genes were selected based on scRNA-seq data and WGCNA. Then, 113 M2 macrophage-related genes were obtained by overlapping the scRNA-seq data and WGCNA results. Nine M2 macrophage-related genes (SMOC2, PLPP1, HES1, STMN1, GPR160, ABCG1, MAZ, MYC, and EPCAM) were screened as prognostic gene signatures. M2 risk score was calculated, the DEGs, Immune score, stromal score, ESTIMATE score, tumor purity, and immune cell infiltration, immune checkpoint expression, and responses of immunotherapy and chemotherapy were identified. And a predictive nomogram was constructed. CCK8, Transwell invasion, and wound healing further verified that M2 macrophages promoted the proliferation, invasion, and migration of PCa (p < 0.05). CONCLUSIONS: We uncovered that M2 macrophages and relevant genes played key roles in promoting the occurrence, development, and metastases of PCa and played as convincing predictors in PCa.
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Biomarcadores de Tumor , Macrófagos , Neoplasias de la Próstata , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Análisis de la Célula Individual/métodos , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Macrófagos/metabolismo , Macrófagos/inmunología , RNA-Seq , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica/métodos , Nomogramas , Análisis de Secuencia de ARN , Análisis de Expresión Génica de una Sola CélulaRESUMEN
The aetiology of bone metastasis in prostate cancer (PCa) remains unclear. This study aims to identify hub genes involved in this process. We utilized machine learning, GO, KEGG, GSEA, Single-cell analysis, ROC methods to identify hub genes for bone metastasis in PCa using the TCGA and GEO databases. Potential drugs targeting these genes were identified. We validated these results using 16 specimens from patients with PCa and analysed the relationship between the hub genes and clinical features. The impact of APOC1 on PCa was assessed through in vitro experiments. Seven hub genes with AUC values of 0.727-0.926 were identified. APOC1, CFH, NUSAP1 and LGALS1 were highly expressed in bone metastasis tissues, while NR4A2, ADRB2 and ZNF331 exhibited an opposite trend. Immunohistochemistry further confirmed these results. The oxidative phosphorylation pathway was significantly enriched by the identified genes. Aflatoxin B1, benzo(a)pyrene, cyclosporine were identified as potential drugs. APOC1 expression was correlated with clinical features of PCa metastasis. Silencing APOC1 significantly inhibited PCa cell proliferation, clonality, and migration in vitro. This study identified 7 hub genes that potentially facilitate bone metastasis in PCa through mitochondrial metabolic reprogramming. APOC1 emerged as a promising therapeutic target and prognostic marker for PCa with bone metastasis.
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Neoplasias Óseas , Proliferación Celular , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata , Humanos , Neoplasias Óseas/secundario , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Biología Computacional/métodos , Proliferación Celular/genética , Línea Celular Tumoral , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Movimiento Celular/genética , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , PronósticoRESUMEN
Gypsum Fibrosum, as a classic heat-clearing medicine, is widely used in the clinical practice of traditional Chinese medicine(TCM). However, debates exist about the material basis and mechanism of its efficacy. Therefore, this paper reviewed the recent research progress in the heat-clearing effect and mechanism of Gypsum Fibrosum and discussed the material basis for the heat-clearing effect of this medicine. Ca~(2+) may inhibit the upward movement of temperature set point by regulating the Na~+/Ca~(2+) level in the heat-regulating center. Moreover, trace elements may inhibit the rise of body temperature by regulating the immune system, promoting the absorption of Ca~(2+), and affecting the synthesis of prostaglandin E2(PGE2). This review aims to enrich the knowledge about the mechanism of Gypsum Fibrosum in clearing heat and provides a scientific basis for the clinical application and further development of Gypsum Fibrosum.
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Medicamentos Herbarios Chinos , Medicamentos Herbarios Chinos/farmacología , Sulfato de Calcio/farmacología , Calor , Medicina Tradicional ChinaAsunto(s)
Carcinoma de Células Renales , Riñón Fusionado , Neoplasias Renales , Laparoscopía , Humanos , Carcinoma de Células Renales/cirugía , Riñón Fusionado/complicaciones , Riñón Fusionado/diagnóstico por imagen , Riñón Fusionado/cirugía , Nefrectomía , Neoplasias Renales/cirugía , Neoplasias Renales/patologíaAsunto(s)
Cistitis , Laparoscopía , Humanos , Cistectomía , Vejiga Urinaria/cirugía , Cistitis/etiología , Cistitis/cirugíaRESUMEN
Circular RNA (circRNA), a type of noncoding RNAs, has been demonstrated to act vital roles in tumorigenesis and cancer deterioration. Although tumor-associated macrophages are involved in tumor malignancy, the interactions between circRNAs and tumor-associated macrophages in prostate cancer (PCa) remain unclear. In the present study, we found that hsa_circ_0094606 (subsequently named circ_0094606) could promote proliferation, epithelial-mesenchymal transition (EMT) as well as migration of PCa cells through cell viability and migration assays and the determination of EMT markers. Mass spectrometry analysis after RNA pull-down experiment identified that circ_0094606 bound to protein arginine methyltransferase 1 (PRMT1) in PCa cells, and further functional assays revealed that circ_0094606 promoted the malignant progression of PCa by binding to PRMT1. Moreover, co-immunoprecipitation (Co-IP), glutathione-S-transferase (GST) pull-down and immunofluorescence showed that PRMT1 mediated arginine methylation of ILF3 to stabilize the protein. Bioinformatics analysis combined with data from RNA-binding protein immunoprecipitation and RNA pull-down suggested that ILF3 could stabilize IL-8 mRNA, which promoted the M2 polarization in coculture study. Finally, in vivo experiments showed that circ_0094606 subserve PCa growth and promoted the M2 polarization of macrophages through the PRMT1/ILF3/IL-8 regulation pathway, supporting circ_0094606 as a potential novel effective target for PCa treatment.
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MicroARNs , Neoplasias de la Próstata , Masculino , Humanos , Metilación , Arginina/genética , Arginina/metabolismo , Interleucina-8/genética , ARN/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Metiltransferasas/genética , Neoplasias de la Próstata/genética , Macrófagos/metabolismo , MicroARNs/genética , Proliferación Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
Circular RNAs (circRNAs) are a type of non-coding RNA that plays a vital role in biology. circRNAs appear to have a role in the development and progression of several malignancies, according to research. However, circRNAs that regulate prostate cancer (PCa) progression are still largely unknown and deserve further exploration. The aim of this study was to investigate the effect of hsa_circ_0070512 on the function and mechanism of PCa. hsa_circ_0070512 was increased in PCa tissues and cells and was mostly found in the cytoplasm of PCa cells. Overexpression of hsa_circ_0070512 considerably increased PCa cell proliferation and migration, whereas silencing of hsa_circ_0070512 greatly decreased PCa cell proliferation and migration. Mechanistically, we show that hsa_circ_0070512 acts as a "molecular sponge" for miR-338-3p and that the miR-338-3p mimics partially block the pro-tumor effects of hsa_circ_0070512. RNA sequencing analysis of PC3 cells stably overexpressing hsa_circ_0070512 revealed that hedgehog was downstream of the signaling pathways of hsa_circ_0070512 and miR-338-3p. Our results implied that hsa_circ_0070512 regulated the hedgehog signaling pathways through miR-338-3p to enhance PCa growth and migration, providing a new diagnostic and therapeutic target for PCa.
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MicroARNs , Neoplasias de la Próstata , Masculino , Humanos , MicroARNs/genética , MicroARNs/metabolismo , ARN Circular/genética , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Neoplasias de la Próstata/genética , Transducción de Señal/genética , Proliferación Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
RATIONALE: TFEB-associated renal cell carcinoma is very rare and belongs to the microphthalmia - associated transcription family translocation renal cell carcinoma. PATIENT CONCERNS: Hospitalized for fever, a 29-year-old male patient had a left kidney lesion without any additional discomfort. DIAGNOSES: Histopathological and immunohistochemical results were corresponding with TFEB renall cell carcinoma features. INTERVENTIONS: Surgical resection of the tumor was performed. OUTCOMES: After 8 months of follow-up, no tumor recurrence was observed. LESSONS: TFEB-associated renal cell carcinoma is rare. The diagnosis is explicit. However, the optimal treatment needs to be further explored.
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Carcinoma de Células Renales , Neoplasias Renales , Masculino , Humanos , Adulto , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/genética , Neoplasias Renales/patología , Translocación Genética , Biomarcadores de Tumor , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Recurrencia Local de NeoplasiaRESUMEN
Bladder cancer (BC) is one of the most common malignancies involving the urinary system. Our previous study demonstrated that cobra venom membrane toxin 12 (MT-12) could effectively inhibit BC cell growth and metastasis and induce apoptosis. However, the specific molecular mechanism remains unknown. In this study, we explored whether MT-12 inhibits BC cell proliferation by inducing autophagy cell death through mitochondrial dysfunction. As a result, MT-12 inhibited proliferation and colony formation in RT4 and T24 cells. In the BC xenograft mouse model, autophagy inhibitor 3-MA alleviated the inhibitory effect of MT-12 on tumor growth. In addition, immunostaining revealed downregulated autophagy in MT-12-treated RT4 and T24 cells. We also found that MT-12 led to dysfunctional mitochondria with decreased mitochondrial membrane potential, mtDNA abundance, and increased ROS production, ultimately inducing autophagic apoptosis via the ROS/JNK/P53 pathway. MT-12 inhibits BC proliferation in vitro and in vivo by enhancing autophagy. MT-12 induces mitochondrial dysfunction and decreases autophagy, leading to increased ROS production, which in turn activates the JNK/p53 pathway, leading to BC apoptosis.
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Prostate cancer (PCa) is one of the most prevalent cancers of the urinary system. In previous research, Kinesin family member 2C (KIF2C), as an oncogene, has been demonstrated to have a key role in the incidence and progression of different cancers. However, KIF2C has not been reported in PCa. We combined data from different databases, including The Cancer Genome Atlas, the Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, and the Genomics of Drug Sensitivity in Cancer database, to explore the potential oncogenic role of KIF2C in PCa through a series of bioinformatics approaches, including analysis of the association between KIF2C and prognosis, clinicopathological features, gene mutations, DNA methylation, immune cell infiltration, and drug resistance. The results showed that KIF2C was significantly up-regulated in PCa. High KIF2C expression was associated with age, pathological stage, lymph node metastases, prostate-specific antigen (PSA), and Gleason score and significantly predicted an unfavorable prognosis in PCa patients. Results from Gene Set Enrichment Analysis (GSEA) suggested that KIF2C was involved in the cell cycle and immune response. KIF2C DNA methylation was reduced in PCa and was inversely linked with KIF2C expression. KIF2C was shown to have a strong relationship with the tumor microenvironment (TME), infiltrating cells, and immune checkpoint genes. Furthermore, high KIF2C expression was significantly resistant to a variety of MAPK signaling pathway-related inhibitors. Our study reveals that KIF2C may be a possible predictive biomarker for assessing prognosis in PCa patients with immune infiltration.
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Neoplasias de la Próstata , Transcriptoma , Análisis de Datos , Perfilación de la Expresión Génica/métodos , Humanos , Cinesinas/genética , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: The epidemiological investigation of different cancer types in the global population has reported a decreased risk of bladder cancer (BLCA) in Parkinson's diseases (PD). SNCA a critical gene in PD pathology have been reported involved in tumorigenesis recently. However, the role of SNCA in BLCA remains unclear. This study aimed to explore the potential value of SNCA as a prognostic diagnostic molecular biomarker in BLCA. METHODS: In this study, we explored the expression pattern, prognostic value and promoter methylation level of SNCA in BLCA by GEPIA2, UALCAN, TCGA, GENT2, GEO and c-BioPortal database. Then, we used LinkedOmics database to obtain the co-expression genes of SNCA for further study by WGCNA. We further investigated the correlations between SNCA expression and six main types of immune cell infiltrations and immune signatures by TIMER. Finally, BLCA cell lines treated with 5-Aza-CdR were used to explore the correlation between increased methylation and downregulated mRNA expression. RESULTS: SNCA was downregulated in tumor tissues in TCGA-BLCA, GENT2 and GEO, which was validated in our cohort by qRT-PCR and immunohistochemistry. SNCA was confirmed as an independent predictor of poor overall survival (OS). LinkedOmics analysis suggested that SNCA regulates cell adhesion molecules, cytokine-cytokine receptor interaction, and complement and coagulation cascades. Twenty-two co-expression gene modules were constructed by WGCNA, and most of them were significantly associated with OS and disease-free survival (DFS). Six key genes (CNTN1, DACT3, MYLK1, PDE2A, RBM24, and ST6GALNAC3) screened also significantly correlated with prognosis. There were significant correlations between SNCA expression and immune infiltrations, especially T cell, suggesting that immune infiltration was one of the reasons for the influence of SNCA on prognosis in BLCA. Analysis by ULACAN and c-BioPortal showed that the promoter methylation of SNCA negatively correlated with its mRNA level. Furthermore, BLCA cell treatment with 5-Aza-CdR revealed that SNCA expression levels were upregulated with decreased methylation. CONCLUSION: Our research showed that SNCA was downregulated in BLCA and negatively correlation with DNA methylation. High SNCA expression was confirmed as an independent risk for prognosis. SNCA probably plays an important role in the infiltration of immune cells, especially with T cells. Thus, SNCA may be a promising prognostic biomarker in BLCA patients.
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Neoplasias de la Vejiga Urinaria , alfa-Sinucleína , Metilación de ADN , Redes Reguladoras de Genes , Humanos , Pronóstico , Regiones Promotoras Genéticas , Proteínas de Unión al ARN/genética , Neoplasias de la Vejiga Urinaria/patología , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
Alpha-synuclein (α-syn), encoded by the SNCA gene, is a major participant in the pathophysiology of Parkinson's disease (PD). Its functions have been reported to be related to apoptosis induction, the elevation of oxidative stress, mitochondrial homeostasis, cell-cycle aberrations, and DNA-related interactions. Evidence obtained in recent studies suggests a possible link between α-syn and cancer development. Bladder cancer (BCa) is the second most common genitourinary malignancy, with the population of survivors of BCa increasing worldwide. In this study, we show that α-syn expression was significantly downregulated in BCa. In vitro and in vivo experiments showed that α-syn could significantly inhibit BCa cell proliferation by arresting the cell cycle in the S phase via upregulation of p53 expression mediated by DNA damages. Further experiments showed that overexpression of α-syn delivered by adeno-associated viruses (AAVs) exerted inhibitory effects on the growth of BCa tumors. These findings indicate that αα-syn is a functional tumor suppressor that can inhibit the proliferation of BCa cells by activating the p53/p21 signaling pathway. Our present study provides insights into the roles of α-syn in BCa and suggests that α-syn may be a novel therapeutic target for the treatment of BCa.
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Neoplasias de la Vejiga Urinaria , alfa-Sinucleína , Dependovirus/genética , Dependovirus/metabolismo , Humanos , Transducción de Señal , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias de la Vejiga Urinaria/patología , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND: Multiomics data analysis based on high-throughput sequencing technology has become a hotspot in tumor investigation. The present study aimed to explore prognostic biomarkers via investigating DNA copy number variation (CNV) and methylation variation (MET) data in prostate cancer. METHODS: We obtained the messenger RNA (mRNA) expression, CNV, and methylated data of prostate adenocarcinoma (PRAD) samples via The Cancer Genome Atlas (TCGA)-PRAD cohort. We calculated and assessed the associations between CNV and RNA sequencing (RNA-seq), and between MET and RNA-seq via Pearson correlation coefficients. We then used the "iCluster" package to perform multigroup cluster analysis with CNVcor gene CNV data, METcor gene methylation data, and CNVcor and METcor gene mRNA data. The univariate Cox analysis was used to screen significant hub genes, and multivariate Cox analysis was used to construct risk a model. The nomogram was constructed based on "rms" package, and the immune infiltrating patterns were compared between high- and low-risk groups. RESULTS: A total of 477 PRAD samples with complete CNV, methylation, mRNA, and matched clinical information were included in our study. A list of 10,073 CNVcor genes and 9841 METcor genes were confirmed with a significance level of P<0.01. We found that CNVcor is more likely to appear on chromosome (chr)8, chr17, and chr10, while METcor is more likely to appear on chr1, chr19, and chr17. Based on the core genes, we finally classified the samples into 4 subtypes, incorporating iC1 (iCluster) (92 samples), iC2 (79 samples), iC3 (165 samples), and iC4 (141 samples). Furthermore, we constructed the prognostic model for PRAD based on the 5 genes (IER3, AOX1, PRKCDBP, UBD, and FBLN5). Nomograms incorporating risk score and other clinical variables were further constructed, and these nomograms exhibited superior predictive ability. We further compared the differential immune infiltrating patterns in 2 risk groups and found significantly low levels of infiltrating cluster of differentiation (CD)8+ T cells in high-risk samples. CONCLUSIONS: Our study integrated the multi-omics data to elucidate the molecular features of PRAD and pivotal genes for predicting prognosis.
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Paris forrestii is a unique plant found in Tibet and Yunnan, China, and total saponins from Paris forrestii (PCT3) contain anticancer steroid glycosides. RNA expression plays an important role in various biological processes. However, the cytotoxicity effects and mechanisms of PCT3 in relation to prostate cancer (PCa) cells have not yet been reported. In the present study, the antitumor activity of PCT3 on PCa cells was evaluated. PCT3 displayed potent anticancer effects toward PCa cells that were similar to the effects of pure saponins from P. forrestii, but PCT3 had less activity in suppressing the prostate epithelial cell line RWPE. Furthermore, using CCK-8 assays, Edu incorporation, colony formation assays, Annexin V/PI assays and western blotting, we found that treatment with 4⯵g/mL PCT3 significantly decreased proliferation and induced apoptosis in PCa cells. Using wound healing and transwell assays, we demonstrated that treatment with 2⯵g/mL PCT3 significantly suppressed the migration and invasion of PCa cells. To explore the molecular mechanisms behind the anticancer effect of PCT3, PCT3 (5⯵g/mL) treated and untreated PCa cells (LNCAP and PC3 cell lines) were analyzed using transcriptomics. Taking the commonly differentially expressed genes (log2FCâ¯>â¯0.585) in both cell lines, 41 mRNAs and 5 lncRNAs were eventually identified. Bioinformatics analysis (GO and KEGG analyses) revealed that some genes involved in classical cell proliferation and apoptosis pathways were aberrantly expressed after PCT3 treatment of PCa cells. By using q-PCR, the expression levels of NEAT1, MALAT1, TIPIN, LYAR, IQGAP3, GINS2, and ZGRF1 were validated as consistent with microarray data, suggesting that these genes might participate in the PCT3 anticancer effect. The present study suggests that PCT3 exhibits an anticancer effect on PCa and reveals some crucial lncRNAs and mRNAs that are involved in the anticancer mechanisms of PCT3 on Pca.