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Bladder cancer is a malignancy characterized by significant heterogeneity. RNA methylation has received an increasing amount of attention in recent years. RNA data were collected from the GEO database, and cell subsets were classified according to specific cell markers. Epithelial, immunological, and fibroblast cells were clustered individually to explore the tumor heterogeneity. To distinguish between malignant and benign cells, the InferCNV R package was employed. The monocle2 R package was used for pseudotime analysis. The Decouple R package was used for transcription factor analysis of each cell subgroup, and PROGENy was used to predict the activity of pathways related to tumors. The target lncRNA was screened for model construction. In addition, the qPCR experiment was used to detect the transcription level of lncRNA. Epithelial cells, fibroblasts, and T cells significantly differ in tumor and normal tissues. The lncRNAs related to m6A/m5C/m1A were intersected to construct the model. Finally, six model lncRNAs (PSMB8-AS1, THUMPD3-AS1, U47924.27, XXbac-B135H6.15, MIR99AHG, and C14orf132) were screened. High-risk individuals were shown to have a better prognosis. qPCR experiments showed that the model lncRNA was differentially expressed between normal and tumor cells. Immunotherapy will be more effective in treating individuals with lower risk than those with higher risk using 4 candidate drugs. The prognostic m6A/m5C/m1A-related lncRNA model was constructed for evaluating the clinical outcomes of bladder cancer patients and guiding clinical medication.
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RNA Longo não Codificante , Neoplasias da Bexiga Urinária , Humanos , Prognóstico , Metilação de RNA , Imunoterapia , Análise de Sequência de RNARESUMO
BACKGROUND: Bladder cancer (BLCA) is a prevalent malignancy worldwide. Anoikis remains a new form of cell death. It is necessary to explore Anoikis-related genes in the prognosis of BLCA. METHODS: We obtained RNA expression profiles from the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases for dimensionality reduction analysis and isolated epithelial cells, T cells and fibroblasts for copy number variation analysis, pseudotime analysis and transcription factor analysis based on R package. We integrated machine-learning algorithms to develop the artificial intelligence-derived prognostic signature (AIDPS). RESULTS: The performance of AIDPS with clinical indicators was stable and robust in predicting BLCA and showed better performance in every validation dataset compared to other models. Mendelian randomization analysis was conducted. Single nucleotide polymorphism (SNP) sites of rs3100578 (HK2) and rs66467677 (HSP90B1) exhibited significant correlation of bladder problem (not cancer) and bladder cancer, whereasSNP sites of rs3100578 (HK2) and rs947939 (BAD) had correlation between bladder stone and bladder cancer. The immune infiltration analysis of the TCGA-BLCA cohort was calculated via the ESTIMATE (i.e. Estimation of STromal and Immune cells in MAlignantTumours using Expression data) algorithm which contains stromal, immune and estimate scores. We also found significant differences in the IC50 values of Bortezomib_1191, Docetaxel_1007, Staurosporine_1034 and Rapamycin_1084 among the high- and low-risk groups. CONCLUSIONS: In conclusion, these findings indicated Anoikis-related prognostic genes in BLCA and constructed an innovative machine-learning model of AIDPS with high prognostic value for BLCA.
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Anoikis , Neoplasias da Bexiga Urinária , Humanos , Anoikis/genética , Inteligência Artificial , Variações do Número de Cópias de DNA , Neoplasias da Bexiga Urinária/genética , AlgoritmosRESUMO
INTRODUCTION: Clear cell renal cell carcinoma (ccRCC) is the most prevalent and aggressive subtype of renal cell carcinoma, originating from renal tubular epithelial cells in the kidney. Hypoxia proves to be a feature commonly observed in solid tumors, leading to increased resistance to treatment and tumor progression. METHODS: scRNA-seq data were procured from GSE159115 data set. We utilized UMAP and NMF algorithm for clustering and dimensionality reduction. The FindAllMarkers function was used to compare various groups and identify potential hypoxia marker genes. A series of in vitro experiments, including CFA, flow cytometry targeting cell cycle, CCK-8, and EDU, was applied to investigate how ANGPTL4 regulated the ccRCC progression. Two cell lines of ccRCC cells, 786-O and Caki, were used for si-ANGPTL4 transfection. RESULTS: We annotated a total of a total of 6 cell clusters, namely ccRCC malignant cells, T cells, endothelial cells, myeloid cells, smooth muscle cells, and B cells. We observed higher levels of hypoxia-score in the ccRCC malignant cells, while lowest hypoxia-score in T and B cells. We detected multiple hypoxia-related subclusters of TME cells in ccRCC, among which S100A4 CD8+ T cells and nonhypoxia CD8+ T cells were found with a marked elevation of T cell inhibitory gene score. We identified that ANGPTL4+ endothelial cells might function as an integrative role in tumor angiogenesis. Multiple TME subclusters showed high potency in stratification of the prognosis of ccRCC patients. Moreover, by a series of in vitro experiment, we found ANGPTL4 regulated the ccRCC cell proliferation, probably through ERK/P38 pathway. CONCLUSION: We discerned multiple hypoxia-related subclusters of TME cells in ccRCC, which displayed distinct functional features and great potency in predicting prognosis of ccRCC patients. We identified the role of ANGPTL4 in regulating ccRCC proliferation via ERK/p38 pathway.
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Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Carcinogênese , Hipóxia/genéticaRESUMO
INTRODUCTION: Prostate cancer is a common cancer among male population. The aberrant expression of histone modifiers has been identified as a potential driving force in numerous cancer types. However, the mechanism of histone modifiers in the development of prostate cancer remains unknown. METHODS: Expression profiles and clinical data were obtained from GSE70769, GSE46602, and GSE67980. Seruat R package was utilized to calculate the gene set enrichment of the histone modification pathway and obtain the Histone score. Least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were employed to identify marker genes with prognostic value. Kaplan-Meier survival analysis was conducted to assess the efficacy of the prognostic model. In addition, microenvironment cell populations counter (MCPcounter), single-sample gene set enrichment analysis (ssGSEA), and xCell algorithms were employed for immune infiltration analysis. Drug sensitivity prediction was performed using oncoPredict R package. RESULTS: We screened differentially expressed genes (DEGs) between Histone-high score (Histone-H) and Histone-low score (Histone-L) groups, which were enriched in RNA splicing and DNA-binding transcription factor binding pathways. We retained four prognostic marker genes, including TACC3, YWHAH, TAF1C and TTLL5. The risk model showed significant efficacy in stratification of the prognosis of prostate cancer patients in both internal and external cohorts (p < .0001 and p = .032, respectively). In addition, prognostic gene YWHAH was infiltrated in abundance of fibroblasts and highly correlated with Entinostat_1593 drug sensitivity score and the value of risk score. CONCLUSION: We innovatively developed a histone modification-related prognostic model with high prognostic potency and identified YWHAH as possible diagnostic and therapeutic biomarkers for prostate cancer. It provides novel insights to address prostate cancer and enhance clinical outcomes, thereby opening up a new avenue for customized treatment alternatives.
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Histonas , Neoplasias da Próstata , Humanos , Masculino , Histonas/genética , Prognóstico , RNA-Seq , Neoplasias da Próstata/genética , Genes cdc , Microambiente Tumoral/genética , Proteínas Associadas aos MicrotúbulosRESUMO
Clear-cell renal cell carcinoma (ccRCC) appears as the most common type of kidney cancer, the carcinogenesis of which has not been fully elucidated. Tumor heterogeneity plays a crucial role in cancer progression, which could be largely deciphered by the implement of scRNA-seq. The bulk and single-cell RNA expression profile is obtained from TCGA and study conducted by Young et al. We utilized UMAP, TSNE, and clustering algorithm Louvain for dimensionality reduction and FindAllMarkers function for determining the DEGs. Monocle2 was utilized to perform pseudo-time series analysis. SCENIC was implemented for transcription factor analysis of each cell subgroup. A series of WB, CFA, CCK-8, and EDU analysis was utilized for the validation of the role of MT2A in ccRCC carcinogenesis. We observed higher infiltration of T/NK and B cells in tumorous tissues, indicating the role of immune cells in ccRCC carcinogenesis. Transcription factor analysis revealed the activation of EOMES and ETS1 in CD8 + T cells, while CAFs were divided into myo-CAFs and i-CAFs, with i-CAFs showing distinct enrichment of ATF3, JUND, JUNB, EGR1, and XBP1. Through cell trajectory analysis, we discerned three distinct stages of cellular evolution, where State2 symbolizes normal renal tubular cells that underwent transitions into State1 and State3 as the CNV score ascended. Functional enrichment examination revealed an amplification of interferon gamma and inflammatory response pathways within tumor cells. The consensus clustering algorithm yielded two molecular subtypes, with cluster 2 being associated with advanced tumor stages and an abundance of infiltrated immune cells. We identified 17 prognostic genes through Cox and LASSO regression models and used them to construct a prognostic model, the efficacy of which was verified in multiple cohorts. Furthermore, we investigated the role of MT2A, one of our hub genes, in ccRCC carcinogenesis, and found it to regulate proliferation and migration of malignant cells. We depicted a detailed single-cell landscape of ccRCC, with special focus on CAFs, endothelial cells, and renal tubular cells. A prognostic model of high stability and accuracy was constructed based on the DEGs. MT2A was found to be actively implicated in ccRCC carcinogenesis, regulating proliferation and migration of the malignant cells.
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Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Células Endoteliais , Análise da Expressão Gênica de Célula Única , Carcinogênese , Neoplasias Renais/genética , MetalotioneínaRESUMO
BACKGROUND: Muscle-invasive bladder cancer (MIBC) is one of the most important type of bladder cancer, with a high morbidity and mortality rate. Studies have found that long non-coding RNA (lncRNA) plays a key role in maintaining genomic instability. However, Identification of lncRNAs related to genomic instability (GIlncRNAs) and their clinical significance in cancers have not been extensively studied yet. METHODS: Here, we downloaded the lncRNA expression profiles, somatic mutation profiles and clinical related data in MIBC patients from The Cancer Genome Atlas (TCGA) database. A lncRNA computational framework was used to find differentially expressed GIlncRNAs. Multivariate Cox regression analysis was used to construct a genomic instability-related lncRNA signature (GIlncSig). Univariate and multivariate Cox analyses were used to assess the independent prognostic for the GIlncSig and other key clinical factors. RESULTS: We found 43 differentially expressed GIlncRNAs and constructed the GIlncSig with 6 GIlncRNAs in the training cohort. The patients were divided into two risk groups. The overall survival of patients in the high-risk group was lower than that in the low-risk group (P < 0.001), which were further verified in the testing cohort and the entire TCGA cohort. Univariate and multivariate Cox regression showed that the GIlncSig was an independent prognostic factor. In addition, the GIlncSig correlated with the genomic mutation rate of MIBC, indicating its potential as a measure of the degree of genomic instability. The GIlncSig was able to divide FGFR3 wild- and mutant-type patients into two risk groups, and effectively enhanced the prediction effect. CONCLUSION: Our study introduced an important reference for further research on the role of GIlncRNAs, and provided prognostic indicators and potential biological therapy targets for MIBC.
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BACKGROUND: The effective treatment and prognosis prediction of bladder cancer (BLCA) remains a medical problem. Ferroptosis is an iron-dependent form of programmed cell death. Ferroptosis is closely related to tumour occurrence and progression, but the prognostic value of ferroptosis-related genes (FRGs) in BLCA remains to be further clarified. In this study, we identified an FRG signature with potential prognostic value for patients with BLCA. METHODS: The corresponding clinical data and mRNA expression profiles of BLCA patients were downloaded from The Cancer Genome Atlas (TCGA). Univariate Cox regression was used to extract FRGs related to survival time, and a Cox regression model was used to construct a multigene signature. Both principal component analysis (PCA) and single-sample gene set enrichment analysis (ssGSEA) were performed for functional annotation. RESULTS: Clinical traits were combined with FRGs, and 15 prognosis-related FRGs were identified by Cox regression. High expression of CISD1, GCLM, CRYAB, SLC7A11, TFRC, ACACA, ZEB1, SQLE, FADS2, ABCC1, G6PD and PGD was related to poor survival in BLCA patients. Multivariate Cox regression was used to construct a prognostic model with 7 FRGs that divided patients into two risk groups. Compared with that in the low-risk group, the overall survival (OS) of patients in the high-risk group was significantly lower (P < 0.001). In multivariate regression analysis, the risk score was shown to be an independent predictor of OS (HR = 1.772, P < 0.01). Receiver operating characteristic (ROC) curve analysis verified the predictive ability of the model. In addition, the two risk groups displayed different immune statuses in ssGSEA and different distributed patterns in PCA. CONCLUSION: Our research suggests that a new gene model related to ferroptosis can be applied for the prognosis prediction of BLCA. Targeting FRGs may be a treatment option for BLCA.
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Biomarcadores Tumorais/genética , Ferroptose , Nomogramas , Neoplasias da Bexiga Urinária/mortalidade , Seguimentos , Perfilação da Expressão Gênica , Humanos , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
Transurethral resection of bladder tumor (TURBT) is the first-line treatment option for non-muscle invasive bladder cancer (NMIBC), but residual tumor often remains after TURBT, thereby leading to cancer recurrence. Here, we introduce combined use of in vivo Raman spectroscopy and in vivo cryoablation as a new approach to detect and remove residual bladder tumor during TURBT. Bladder cancer (BCa) patients treated with TURBT at our urological department between Dec 2019 and Jan 2021 were collected. First, Raman signals were collected from 74 BCa patients to build reference spectra of normal bladder tissue and of bladder cancers of different pathological types. Then, another 53 BCa patients were randomly categorized into two groups, 26 patients accepted traditional TURBT, 27 patients accepted TURBT followed by Raman scanning and cryoablation if Raman detected existence of residual tumor. The recurrence rates of the two groups until Oct 2022 were compared. Raman was capable of discriminating normal bladder tissue and BCa with a sensitivity and specificity of 90.5% and 80.8 %; and discriminating invasive (T1, T2) and noninvasive (Ta) BCa with a sensitivity and specificity of 83.3 % and 87.3 %. During follow-up, 2 in 27 patients had cancer recurrence in Raman-Cryoablation group, while 8 in 26 patients had cancer recurrence in traditional TURBT group. Combined use of Raman and cryoablation significantly reduced cancer recurrence (p = 0.0394). Raman and cryoablation can serve as an adjuvant therapy to TURBT to improve therapeutic effects and reduce recurrence rate.
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Criocirurgia , Neoplasias da Bexiga Urinária , Humanos , Neoplasia Residual/cirurgia , Análise Espectral Raman , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologiaRESUMO
BACKGROUND: Bladder cancer (BCa) is among the most prevalent malignant tumors affecting the urinary system. Due to its highly recurrent nature, standard treatments such as surgery often fail to significantly improve patient prognosis. Our research aims to predict prognosis and identify precise therapeutic targets for novel treatment interventions. METHODS: We collected and screened genes related to the TGF-ß signaling pathway and performed unsupervised clustering analysis on TCGA-BLCA samples based on these genes. Our analysis revealed two novel subtypes of bladder cancer with completely different biological characteristics, including immune microenvironment, drug sensitivity, and more. Using machine learning classifiers, we identified SMAD6 as a hub gene contributing to these differences and further investigated the role of SMAD6 in bladder cancer in the single-cell transcriptome data. Additionally, we analyzed the relationship between SMAD6 and immune checkpoint genes. Finally, we performed a series of in vitro assays to verify the function of SMAD6 in bladder cancer cell lines. RESULTS: We have revealed two novel subtypes of bladder cancer, among which C1 exhibits a worse prognosis, lower drug sensitivity, a more complex tumor microenvironment, and a 'colder' immune microenvironment compared to C2. We identified SMAD6 as a key gene responsible for the differences and further explored its impact on the molecular characteristics of bladder cancer. Through in vitro experiments, we found that SMAD6 promoted the prognosis of BCa patients by inhibiting the proliferation and migration of BCa cells. CONCLUSION: Our study reveals two novel subtypes of BCa and identifies SMAD6 as a highly promising therapeutic target.
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Aprendizado de Máquina , Proteína Smad6 , Microambiente Tumoral , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Prognóstico , Proteína Smad6/genética , Proteína Smad6/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Proliferação de Células , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão GênicaRESUMO
Sunitinib remains the preferred systemic treatment option for specific patients with advanced RCC who are ineligible for immune therapy. However, it's essential to recognize that Sunitinib fails to elicit a favourable response in all patients. Moreover, most patients eventually develop resistance to Sunitinib. Therefore, identifying new targets associated with Sunitinib resistance is crucial. Utilizing multiple datasets from public cohorts, we conducted an exhaustive analysis and identified a total of 8 microRNAs and 112 mRNAs displaying significant expression differences between Sunitinib responsive and resistant groups. A particular set of six genes, specifically NIPSNAP1, STK40, SDC4, NEU1, TBC1D9, and PLAUR, were identified as highly significant via WGCNA. To delve deeper into the resistance mechanisms, we performed additional investigations using cell, molecular, and flow cytometry tests. These studies confirmed PLAUR's pivotal role in fostering Sunitinib resistance, both in vitro and in vivo. Our findings suggest that PLAUR could be a promising therapeutic target across various cancer types. In conclusion, this investigation not only uncovers vital genes and microRNAs associated with Sunitinib resistance in RCC but also introduces PLAUR as a prospective therapeutic target for diverse cancers. The outcomes contribute to advancing personalized healthcare and developing superior therapeutic strategies.Communicated by Ramaswamy H. Sarma.
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BACKGROUND: Recent research underscores the pivotal role of immune checkpoints as biomarkers in colorectal cancer (CRC) therapy, highlighting the dynamics of resistance and response to immune checkpoint inhibitors. The impact of epigenetic alterations in CRC, particularly in relation to immune therapy resistance, is not fully understood. METHODS: We integrated a comprehensive dataset encompassing TCGA-COAD, TCGA-READ, and multiple GEO series (GSE14333, GSE37892, GSE41258), along with key epigenetic datasets (TCGA-COAD, TCGA-READ, GSE77718). Hierarchical clustering, based on Euclidean distance and Ward's method, was applied to 330 primary tumor samples to identify distinct clusters. The immune microenvironment was assessed using MCPcounter. Machine learning algorithms were employed to predict DNA methylation patterns and their functional enrichment, in addition to transcriptome expression analysis. Genomic mutation profiles and treatment response assessments were also conducted. RESULTS: Our analysis delineated a specific tumor cluster with CpG Island (CGI) methylation, termed the Demethylated Phenotype (DMP). DMP was associated with metabolic pathways such as oxidative phosphorylation, implicating increased ATP production efficiency in mitochondria, which contributes to tumor aggressiveness. Furthermore, DMP showed activation of the Myc target pathway, known for tumor immune suppression, and exhibited downregulation in key immune-related pathways, suggesting a tumor microenvironment characterized by diminished immunity and increased fibroblast infiltration. Six potential therapeutic agents-lapatinib, RDEA119, WH.4.023, MG.132, PD.0325901, and AZ628-were identified as effective for the DMP subtype. CONCLUSION: This study unveils a novel epigenetic phenotype in CRC linked to resistance against immune checkpoint inhibitors, presenting a significant step toward personalized medicine by suggesting epigenetic classifications as a means to identify ideal candidates for immunotherapy in CRC. Our findings also highlight potential therapeutic agents for the DMP subtype, offering new avenues for tailored CRC treatment strategies.
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Neoplasias Colorretais , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/tratamento farmacológico , Microambiente Tumoral/genética , Metilação de DNA/genética , Ilhas de CpG/genética , Epigênese Genética , Análise por Conglomerados , Mutação/genética , Perfilação da Expressão Gênica , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologiaRESUMO
Bladder cancer (BC) is a common malignancy in males, and currently lacks ideal therapeutic approaches. Exploring emerging therapeutic targets from the perspective of endogenous peptides to improve the prognosis of bladder cancer patients holds promise. In this study, we have identified CTSGDP-13, a novel endogenous peptide, which demonstrates potential anti-cancer effects in BC. Our findings reveal that CTSGDP-13 can promote ferroptosis in BC cells, both in vitro and in vivo, leading to the inhibition of BC progression. Furthermore, we have identified TRIM25 as a downstream regulatory target of CTSGDP-13. The expression of TRIM25 is significantly upregulated in BC, and its inhibition of ferroptosis promotes BC progression. Mechanistic studies have shown that CTSGDP-13 promotes the ubiquitination and subsequent degradation of TRIM25 by disrupting its interaction with the deubiquitinase USP7. Further investigations indicate that CTSGDP-13 promotes ferroptosis in BC by regulating the USP7/TRIM25/KEAP1 axis. The elucidation of the functional mechanisms of natural CTSGDP-13 and TRIM25 holds promise in providing valuable therapeutic targets for BC diagnosis and treatment.
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Ferroptose , Neoplasias da Bexiga Urinária , Masculino , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch , Micropeptídeos , Peptidase 7 Específica de Ubiquitina , Fator 2 Relacionado a NF-E2 , Neoplasias da Bexiga Urinária/patologiaRESUMO
We have previously demonstrated abnormal gut microbial composition in castration-resistant prostate cancer (CRPC) patients, here we revealed the mechanism of gut microbiota-derived short-chain fatty acids (SCFAs) as a mediator linking CRPC microbiota dysbiosis and prostate cancer (PCa) progression. By using transgenic TRAMP mouse model, PCa patient samples, in vitro PCa cell transwell and macrophage recruitment assays, we examined the effects of CRPC fecal microbiota transplantation (FMT) and SCFAs on PCa progression. Our results showed that FMT with CRPC patients' fecal suspension increased SCFAs-producing gut microbiotas such as Ruminococcus, Alistipes, Phascolarctobaterium in TRAMP mice, and correspondingly raised their gut SCFAs (acetate and butyrate) levels. CRPC FMT or SCFAs supplementation significantly accelerated mice's PCa progression. In vitro, SCFAs enhanced PCa cells migration and invasion by inducing TLR3-triggered autophagy that further activated NF-κB and MAPK signalings. Meanwhile, autophagy of PCa cells released higher level of chemokine CCL20 that could reprogramme the tumor microenvironment by recruiting more macrophage infiltration and simultaneously polarizing them into M2 type, which in turn further strengthened PCa cells invasiveness. Finally in a cohort of 362 PCa patients, we demonstrated that CCL20 expression in prostate tissue was positively correlated with Gleason grade, pre-operative PSA, neural/seminal vesical invasion, and was negatively correlated with post-operative biochemical recurrence-free survival. Collectively, CRPC gut microbiota-derived SCFAs promoted PCa progression via inducing cancer cell autophagy and M2 macrophage polarization. CCL20 could become a biomarker for prediction of prognosis in PCa patients. Intervention of SCFAs-producing microbiotas may be a useful strategy in manipulation of CRPC.
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Autofagia , Bacteroidetes , Ácidos Graxos Voláteis , Microbioma Gastrointestinal , Macrófagos , Neoplasias de Próstata Resistentes à Castração , Ruminococcus , Veillonellaceae , Ácidos Graxos Voláteis/metabolismo , Progressão da Doença , Macrófagos/patologia , Polaridade Celular , Ruminococcus/metabolismo , Neoplasias de Próstata Resistentes à Castração/microbiologia , Neoplasias de Próstata Resistentes à Castração/patologia , Camundongos Transgênicos , Bacteroidetes/metabolismo , Veillonellaceae/metabolismo , Transplante de Microbiota Fecal , Humanos , Masculino , Animais , CamundongosRESUMO
INTRODUCTION: Gaining a deeper insight into the single-cell RNA sequencing (scRNA-seq) results of bladder cancer (BLCA) provides a transcriptomic profiling of individual cancer cells, which may disclose the molecular mechanisms involved in BLCA carcinogenesis. METHODS: scRNA data were obtained from GSE169379 dataset. We used the InferCNV software to determine the copy number variant (CNV) with normal epithelial cells serving as the reference, and performed the pseudo-timing analysis on subsets of epithelial cell using Monocle3 software. Transcription factor analysis was conducted using the Dorothea software. Intercellular communication analysis was performed using the Liana software. Cox analysis and LASSO regression were applied to establish a prognostic model. RESULTS: We investigated the heterogeneity of tumors in four distinct cell types of BLCA cancer, namely immune cells, endothelial cells, epithelial cells, and fibroblasts. We evaluated the transcription factor activity of different immune cells in BLCA and identified significant enrichment of TCF7 and TBX21 in CD8+ T cells. Additionally, we identified two distinct subtypes of cancer-associated fibroblasts (CAFs), namely iCAFs and myoCAFs, which exhibited distinct communication patterns. Using sub-cluster and cell trajectory analyses, we identified different states of normal-to-malignant cell transformation in epithelial cells. TF analysis further revealed high activation of MYC and SOX2 in tumor cells. Finally, we identified five model genes (SLCO3A1, ANXA1, TENM3, EHBP1, LSAMP) for the development of a prognostic model, which demonstrated high effectiveness in stratifying patients across seven different cohorts. CONCLUSIONS: We have developed a prognostic model that has demonstrated significant efficacy in stratifying patients with BLCA.
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Células Endoteliais , Neoplasias da Bexiga Urinária , Humanos , Prognóstico , Sequência de Bases , Neoplasias da Bexiga Urinária/genética , Fatores de Transcrição , Microambiente Tumoral , Proteínas de Membrana , Proteínas do Tecido NervosoRESUMO
G protein-coupled receptors (GPCRs) are a class of receptors on cell membranes that regulate various biological processes in cells, such as cell proliferation, differentiation, migration, apoptosis, and metabolism, by interacting with G proteins. However, the role of G protein-coupled receptors in predicting the prognosis of renal clear cell carcinoma is still unknown. The transcriptome data and clinical profiles of renal clear cell carcinoma patients, were downloaded from TCGA databases, and the validation group data were downloaded from number GSE167573, including 63 tumor samples and 14 normal samples. Single-cell RNA sequencing data were downloaded from the GEO database, No. GSE152938 and selected samples were used for GSEA enrichment analysis, WGCNA subgroup analysis, single-cell data analysis, and mutation analysis to explore the role of G protein-coupled receptor-related genes in the diagnosis and prognosis of renal clear cell carcinoma and to verify their reliability with cellular experiments. Finally, this study establishes a disease model based on G protein-coupled receptor-related genes, which may help to propose targeted therapeutic regimens in different strata of renal cell carcinoma patients.Author names: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author: Given name [Lisa Jia] Last name [Tran].It's ok!
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Background: The influences of blood lipids and lipid-regulatory medications on the risk of bladder cancer have long been suspected, and previous findings remain controversial. We aimed to assess the causality between blood lipids or lipid-regulatory medications and bladder cancer susceptibility by means of a comprehensive Mendelian Randomization (MR) study. Methods: Genetic proxies from genome-wide association studies (GWAS) of four blood lipid traits and lipid-lowering variants in genes encoding the targets of lipid-regulatory medications were employed. The largest ever GWAS data of blood lipids and bladder cancer involving up to 440,546 and 205,771 individuals of European ancestry were extracted from UK Biobank and FinnGen Project Round 6, respectively. A two-sample bidirectional MR study was performed using the inverse variance weighted as the main method. The heterogeneity, horizontal pleiotropy, MR Steiger, and leave-one-out analyses were also conducted as sensitivity tests. Results: There was indicative evidence that genetically predicted low-density lipoprotein cholesterol (LDL-C) affected bladder cancer susceptibility based on 146 single nucleotide polymorphisms (SNPs) with an odds ratio (OR) of 0.776 (95% confidence interval [CI] = 0.625-0.965, p = 0.022). However, this result became non-significant after two SNPs that possibly drove the effect were removed as demonstrated by leave-one-out analysis. The reversed MR analysis suggested that bladder cancer could not affect serum lipid levels. No causal relationship was found between the lipid-lowering effect of lipid-regulatory medications (fibrates, probucol, statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, and evinacumab) and the risk of bladder cancer. No heterogeneity or pleiotropy was found (all p > 0.05). Conclusion: This MR study revealed for the first time, using the most recent and comprehensive GWAS data to date, that genetically predicted total cholesterol (TC) and the lipid-lowering effect of lipid-regulatory medications had no causal association with bladder cancer susceptibility. We also verified claims from early studies that low-density lipoprotein cholesterol (HDL-C), LDL-C, and triglyceride (TG) are not related to bladder cancer susceptibility either. The current study indicated that lipid metabolism may not be as important in the tumorigenesis of bladder cancer as previously believed.
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Background: Tumor immunological heterogeneity potentially influences the prognostic disparities among patients with clear cell renal cell carcinoma (ccRCC); however, there is a lack of macroscopic imaging tools that can be used to predict immune-related gene expression in ccRCC. Methods: A novel non-invasive radiogenomics biomarker was constructed for immune-related gene expression in ccRCC. First, 520 ccRCC transcriptomic datasets from The Cancer Genome Atlas (TCGA) were analyzed using a non-negative matrix decomposition (NMF) clustering to identify immune-related molecular subtypes. Immune-related prognostic genes were analyzed through Cox regression and Gene Set Enrichment Analysis (GSEA). We then built a risk model based on an immune-related gene subset to predict prognosis in patients with ccRCC. CT images corresponding to the ccRCC patients in The Cancer Imaging Archive (TCIA) database were used to extract radiomic features. To stratify immune-related gene expression levels, extracted radiogenomics features were identified according to standard consecutive steps. A nomogram was built to combine radiogenomics and clinicopathological information through multivariate logistic regression to further enhance the radiogenomics model. Mann-Whitney U test and ROC curves were used to assess the effectiveness of the radiogenomics marker. Results: NMF methods successfully clustered patients into diverse subtypes according to gene expression levels in the tumor microenvironment (TME). The relative abundance of 10 immune cell populations in each tissue was also analyzed. The immune-related genomic signature (consisting of eight genes) of the tumor was shown to be significantly associated with survival in patients with ccRCC in TCGA database. The immune-related genomic signature was delineated by grouping the signature expression as either low- or high-risk. Using TCIA database, we constructed a radiogenomics biomarker consisting of 11 radiomic features that were optimal predictors of immune-related gene signature expression levels, which demonstrated AUC (area under the ROC curve) values of 0.76 and 0.72 in the training and validation groups, respectively. The nomogram built by combining radiomics and clinical pathological information could further improve the predictive efficacy of the radiogenomics model (AUC = 0.81, 074). Conclusions: The novel prognostic radiogenomics biomarker achieved excellent correlation with the immune-related gene expression status of patients with ccRCC and could successfully stratify the survival status of patients in TCGA database. It is anticipated that this work will assist in selecting precise clinical treatment strategies. This study may also lead to precise theranostics for patients with ccRCC in the future.
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Carcinoma de Células Renais , Neoplasias Renais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Nomogramas , Prognóstico , Microambiente Tumoral/genéticaRESUMO
Treatment of urethral mucosa defects is a major challenge in urology. Synthetic materials or autologous mucosa does not provide satisfactory treatment options for long-term or large urethral mucosa defects. In response to this problem, we used autologous adipose-derived stem cells (ADSCs) to synthesize cell sheets in vitro for repairing urethral mucosa defect models. In order to monitor the localization and distribution of cell sheets in vivo, cells and sheets were labeled with indocyanine green (ICG) and the second near-infrared (NIR-II) fluorescence imaging was performed. ICG-based NIR-II imaging can successfully track ADSCs and sheets in vivo up to 8 W. Then, rabbit urethral mucosa defect models were repaired with ICG-ADSCs sheets. At 3 months after operation, retrograde urethrography showed that ADSC sheets could effectively repair urethral mucosa defect and restore urethral patency. Histological analysis showed that in ADSC sheet groups, continuous epithelial cells covered the urethra at the transplantation site, and a large number of vascular endothelial cells could also be seen. In the cell-free sheet group, there was no continuous epithelial cell coverage at the repair site of the urethra, and the expression of pro-inflammatory factor TNF-α was increased. It shows that the extracellular matrix alone without cells is not suitable for repairing urethral defects. Surviving ADSCs in the sheets may play a key role in the repair process. This study provides a new tracing method for tissue engineering to dynamically track grafts using an NIR-II imaging system. The ADSC sheets can effectively restore the structure and function of the urethra. It provides a new option for the repair of urethral mucosa defects.
Assuntos
Verde de Indocianina , Uretra , Animais , Coelhos , Uretra/diagnóstico por imagem , Uretra/cirurgia , Uretra/patologia , Verde de Indocianina/metabolismo , Células Endoteliais , Células-Tronco/metabolismo , MucosaRESUMO
Background: Breast cancer (BC) is the most common malignant tumour, and its heterogeneity is one of its major characteristics. N6-methyladenosine (m6A), N1-methyladenosine (m1A), alternative polyadenylation (APA), and adenosine-to-inosine (A-to-I) RNA editing constitute the four most common adenosine-associated RNA modifications and represent the most typical and critical forms of epigenetic regulation contributing to the immunoinflammatory response, tumorigenesis and tumour heterogeneity. However, the cross-talk and potential combined profiles of these RNA-modified proteins (RMPs) in multivariate prognostic patterns of BC remain unknown. Methods: A total of 48 published RMPs were analysed and found to display significant expression alterations and genomic mutation rates between tumour and normal tissues in the TCGA-BRCA cohort. Data from 4188 BC patients with clinical outcomes were downloaded from the Gene Expression Omnibus (GEO), the Cancer Genome Atlas (TCGA), and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), normalized and merged into one cohort. The prognostic value and interconnections of these RMPs were also studied. The four prognosis-related genes (PRGs) with the greatest prognostic value were then selected to construct diverse RMP-associated prognostic models through univariate Cox (uniCox) regression analysis, differential expression analysis, Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox (multiCox) regression. Alterations in biological functional pathways, genomic mutations, immune infiltrations, RNAss scores and drug sensitivities among different models, as well as their prognostic value, were then explored. Results: Utilizing a large number of samples and a comprehensive set of genes contributing to adenosine-associated RNA modification, our study revealed the joint potential bio-functions and underlying features of these diverse RMPs and provided effective models (PRG clusters, gene clusters and the risk model) for predicting the clinical outcomes of BC. The individuals with higher risk scores showed poor prognoses, cell cycle function enrichment, upregulation of stemness scores, higher tumour mutation burdens (TMBs), immune activation and specific drug resistance. This work highlights the significance of comprehensively examining post-transcriptional RNA modification genes. Conclusion: Here, we designed and verified an advanced forecasting model to reveal the underlying links between BC and RMPs and precisely predict the clinical outcomes of multivariate prognostic patterns for individuals.
RESUMO
Several studies have found that pathological imbalance of alterative splicing (AS) events is associated with cancer susceptibility. carcinogenicity. Nevertheless, the relationship between heritable variation in AS events and carcinogenicity has not been extensively explored. Here, we downloaded AS event signatures, transcriptome profiles, and matched clinical information from The Cancer Genome Atlas (TCGA) database, identified the prognostic AS-related events via conducting the univariate Cox regression algorism. Subsequently, the prognostic AS-related events were further reduced by the least absolute shrinkage and selection operator (LASSO) logistic regression model, and employed for constructing the risk model. Single-sample (ssGSEA), ESTIMATE, and the CIBERSORT algorithms were conducted to evaluate tumor microenvironment status. CCK8, cell culture scratch, transwell invasion assays and flow cytometry were conducted to confirm the reliability of the model. We found 2751 prognostic-related AS events, and constructed a risk model with seven prognostic-related AS events. Compared with high-risk score patients, the overall survival rate of the patients with low-risk score was remarkably longer. Besides, we further found that risk score was also closely related to alterations in immune cell infiltration and immunotherapeutic molecules, indicating its potential as an observation of immune infiltration and clinical response to immunotherapy. In addition, the downstream target gene (DYM) could be a promising prognostic factor for bladder cancer. Our investigation provided an indispensable reference for ulteriorly exploring the role of AS events in the tumor microenvironment and immunotherapy efficiency, and rendered personalized prognosis monitoring for bladder cancer.