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Recent research emphasised the indispensable role of histone lactylation in the activation of hepatic stellate cells. The VHL mutation is extremely common in clear cell renal cell carcinoma, which normally causes a metabolic shift in cancer cells and increases lactate production, eventually creating a lactate-enriched tumour microenvironment. Cancer-associated fibroblasts (CAFs) promote tumour progression, which is also vital in clear cell renal cell carcinoma. Therefore, this study investigated histone lactylation in CAFs and its impact on patient survival. Multiomics technology was employed to determine the role of histone lactylation-related genes in the evolution of CAFs which correlated with the function and molecular signatures of CAFs. The results suggested that TIMP1 was the hub gene of histone lactylation-related genes in clear cell renal cell carcinoma.
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O-GlcNAc transferase (OGT) acts in the development of various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, we found that OGT was upregulated in ccRCC and this upregulation was associated with a worse survival. Moreover, OGT promoted the proliferation, clone formation, and invasion of VHL-mutated ccRCC cells. Mechanistically, OGT increased the protein level of hypoxia-inducible factor-2α (HIF-2α) (the main driver of the clear cell phenotype) by repressing ubiquitinâproteasome system-mediated degradation. Interestingly, the OGT/HIF-2α axis conferred ccRCC a high sensitivity to ferroptosis. In conclusion, OGT promotes the progression of VHL-mutated ccRCC by inhibiting the degradation of HIF-2α, and agents that can modulate the OGT/HIF-2α axis may exert therapeutic effects on mutated VHL ccRCC.
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Clear cell renal cell carcinoma (ccRCC) poses clinical challenges due to its varied prognosis, tumor microenvironment attributes, and responses to immunotherapy. We established a novel Programmed Cell Death-related Signature (PRS) for ccRCC assessment, derived through the Least Absolute Shrinkage and Selection Operator (LASSO) regression method. We validated PRS using the E-MTAB-1980 dataset and created PCD-related clusters via non-negative matrix factorization (NMF). Our investigation included an in-depth analysis of immune infiltration scores using various algorithms. Additionally, we integrated data from the Cancer Immunome Atlas (TCIA) for ccRCC immunotherapy insights and leveraged the Genomics of Drug Sensitivity in Cancer (GDSC) database to assess drug sensitivity models. We complemented our findings with single-cell sequencing data and employed the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and qRT-PCR to compare gene expression profiles between cancerous and paracancerous tissues. PRS serves as a valuable tool for prognostication, immune characterization, tumor mutation burden estimation, immunotherapy response prediction, and drug sensitivity assessment in ccRCC. We identify five genes with significant roles in cancer promotion and three genes with cancer-suppressive properties, further validated by qRT-PCR and CPTAC analyses, showcasing gene expression differences in ccRCC tissues. Our study introduces an innovative PCD model that amalgamates diverse cell death patterns to provide accurate predictions for clinical outcomes, mutational profiles, and immune characteristics in ccRCC. Our findings hold promise for advancing personalized treatment strategies in ccRCC patients.
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Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/terapia , Proteômica , Morte Celular , Prognóstico , Imunoterapia , Neoplasias Renais/genética , Neoplasias Renais/terapia , Microambiente Tumoral/genéticaRESUMO
Background: Reprogramming in glutamine metabolism is a hallmark of cancers, while its role in cutaneous melanoma has not been studied at great length. Methods: Here, we constructed a glutamine metabolism-related prognostic signature in cutaneous melanoma with a variety of bioinformatics methods according to the glutamine metabolism regulatory molecules. Moreover, experimental verification was carried out for the key gene. Results: We have identified two subgroups of cutaneous melanoma patients, each with different prognoses, immune characteristics, and genetic mutations. GOT2 was the most concerned key gene among the model genes. We verified its role in promoting tumor cell proliferation by CCK-8 and clone formation assays. Conclusion: Our study cast new light on the prognosis of cutaneous melanoma, and the internal mechanism regulating glutamine metabolism of GOT2 may provide a new avenue for treating the cutaneous melanoma disease precisely.
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Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes ferroptosis resistance in solid tumors in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which promotes tumor ferroptosis under hypoxia, HIF-1α is the main driver of hypoxia-induced ferroptosis resistance. Mechanistically, HIF-1α-induced lactate contributes to ferroptosis resistance in a pH-dependent manner that is parallel to the classical SLC7A11 and FSP1 systems. In addition, HIF-1α also enhances transcription of SLC1A1, an important glutamate transporter, and promotes cystine uptake to promote ferroptosis resistance. In support of the role of hypoxia in ferroptosis resistance, silencing HIF-1α sensitizes mouse solid tumors to ferroptosis inducers. In conclusion, our results reveal a mechanism by which hypoxia drives ferroptosis resistance and identify the combination of hypoxia alleviation and ferroptosis induction as a promising therapeutic strategy for solid tumors.
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Transportador 3 de Aminoácido Excitatório , Ferroptose , Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias , Animais , Camundongos , Hipóxia Celular , Linhagem Celular Tumoral , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Ácido Láctico , Neoplasias/genética , Neoplasias/patologia , Microambiente Tumoral , Transportador 3 de Aminoácido Excitatório/genéticaRESUMO
It has been reported that heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) is highly expressed in prostate cancer (PCa) and associated with poor prognosis of patients with PCa. Nevertheless, the specific mechanism underlying HNRNPA2B1 functions in PCa remains not clear. In our study, we proved that HNRNPA2B1 promoted the progression of PCa through in vitro and in vivo experiments. Further, we found that HNRNPA2B1 induced the maturation of miR-25-3p/miR-93-5p by recognizing primary miR-25/93 (pri-miR-25/93) through N6-methyladenosine (m6A)-dependent manner. In addition, both miR-93-5p and miR-25-3p were proven as tumor promoters in PCa. Interestingly, by mass spectrometry analysis and mechanical experiments, we found that casein kinase 1 delta (CSNK1D) could mediate the phosphorylation of HNRNPA2B1 to enhance its stability. Moreover, we further proved that miR-93-5p targeted BMP and activin membrane-bound inhibitor (BAMBI) mRNA to reduce its expression, thereby activating transforming growth factor ß (TGF-ß) pathway. At the same time, miR-25-3p targeted forkhead box O3 (FOXO3) to inactivate FOXO pathway. These results collectively indicated that CSNK1D stabilized HNRNPA2B1 facilitates the processing of miR-25-3p/miR-93-5p to regulate TGF-ß and FOXO pathways, resulting in PCa progression. Our findings supported that HNRNPA2B1 might be a promising target for PCa treatment.
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Caseína Quinase Idelta , MicroRNAs , Neoplasias da Próstata , Masculino , Humanos , MicroRNAs/metabolismo , Caseína Quinase Idelta/metabolismo , Fosforilação , Linhagem Celular Tumoral , Neoplasias da Próstata/patologia , Fator de Crescimento Transformador beta/metabolismo , Proliferação de Células/genéticaRESUMO
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC). Many ccRCCs are diagnosed at an advanced stage due to the lack of early symptoms, with a high mortality rate and a poor prognosis. The occurrence and development of ccRCC are closely related to metabolic disorders. This study aims to explore the relationship between metabolic genes and prognosis, immune microenvironment, and tumor development of ccRCC. Using data from TCGA, GEO, and ArrayExpress, we successfully established a risk model (riskScore) based on 4 metabolic genes (MGs) that can accurately predict the prognosis and immune microenvironment of ccRCCs. In addition, we determined the role of PAFAH2 in suppressing tumor cell proliferation and migration in ccRCC in vitro. Our research may shed new light on ccRCC patients' prognosis and treatment management.
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Immune microenvironment could affect the biological progress in prostate cancer (PCa) through N6 methyl adenosine (m6A) methylation. The purpose of this study was to investigate the crosstalk between m6A methylation and immune microenvironment and explore potential biomarkers to improve the immunotherapeutic response. Firstly, according to 11 differentially expressed m6A genes between normal and tumor samples, PCa patients were divided into immune microenvironment subtype 1 (IMS1) and IMS2 based on m6A gene profiles extracted from The Cancer Genome Atlas (TCGA) database. IMS2 showed an immune "cold" phenotype with worse prognoses, and HNRNPC was identified as the biomarker of IMS2 by the protein-protein interaction network. Furthermore, through bioinformatics analyses and in vitro experiments, we found that HNRNPC-high patients showed a suppressive immune-infiltrating tumor microenvironment with a higher infiltration of regulatory T (Treg) cells. Finally, we cocultured transfected PCa cells with peripheral blood mononuclear cells (PBMC) and verified that HNRNPC inhibits tumor immunity by elevating the activation of Treg cells and suppression of effector CD8 T cell. In conclusion, we identified a "cold" immune phenotype in PCa, and HNRNPC regulating the activation of Treg cells. Activation of the immune microenvironment through targeting HNRNPC may be a potential therapeutic option for advanced PCa.
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Neoplasias da Próstata , Linfócitos T Reguladores , Masculino , Humanos , Leucócitos Mononucleares , Microambiente Tumoral/genética , Neoplasias da Próstata/genética , Adenosina , Ribonucleoproteínas Nucleares Heterogêneas Grupo CRESUMO
Ureteral stricture disease (USD) is a common urologic condition. Patients with ureteral stricture disease may suffer from ipsilateral flank pain, nausea, urinary calculi, infection, and impaired renal function. The treatments of USD include surgery, followed by implantation of the ureteral stent to aid the drainage of the urine. The traditional ureteral stent may sometimes cause urological infection, encrustation, and discomfort. To decrease the complication of the ureteral stent, we modified the structure and material based on the traditional ureteral stent. The traditional nondegradable Double-J shape tubular ureteral stent was turned into the biodegradable mesh ureteral stent. The modified mesh ureteral stent and Double-J ureteral stent were inserted into the ureters of the USD animals, respectively. The results of the gross morphology, serology, urinalysis, histology, microstructure, et al. demonstrated that modified mesh ureteral stent has a favorable ability in supporting the ureter and has no effect on cell proliferation, migration, apoptosis, and cell cycle of the human uroepithelial cells. The mesh ureteral stent could relieve ureter obstruction and can be slowly biodegraded after 3-5 months of implantation without the need for a second surgery to remove the stent. Compared to the Double-J ureteral stent, the modified mesh ureteral stent has a lower rate of urinary tract infection and less encrustation. It is expected to be an alternative treatment approach for USD. However, due to the limited number of animals and clinical data, further study focused on the application value in clinical practice are essential. STATEMENT OF SIGNIFICANCE: This study demonstrates: 1. A modified biodegradable mesh ureteral stent; 2. Without the need for a second surgery to remove the stent; 3. A lower rate of urinary tract infection and less encrustation than a double-J ureteral stent; 4. An alternative treatment approach for USD.
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Ureter , Obstrução Ureteral , Infecções Urinárias , Animais , Humanos , Ureter/cirurgia , Constrição Patológica/patologia , Telas Cirúrgicas/efeitos adversos , Obstrução Ureteral/cirurgia , Obstrução Ureteral/etiologia , Obstrução Ureteral/patologia , Stents/efeitos adversos , Infecções Urinárias/complicações , Infecções Urinárias/patologiaRESUMO
Metabolic reprogramming is critical for the setup of the tumor microenvironment (TME). Glutamine has slipped into the focus of research of cancer metabolism, but its role in clear cell renal cell carcinoma (ccRCC) remains vague. Our study aimed to investigate the regulatory mechanism of glutamine in ccRCC and its prognostic value. Gene expression profiles and clinical data of ccRCC patients were obtained from The Cancer Genome Atlas database (TCGA) and Gene Expression Omnibus (GEO) database. Kaplan-Meier survival analysis was used for survival analysis. Consensus clustering was used to extract differentially expressed genes (DEGs) related to glutamine metabolism. Functional analyses, including gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA), were conducted to elucidate the functions and pathways involved in these DEGs. The single-sample GSEA and Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) methods were applied to estimate the immune infiltration in the TMEs of two clusters. The univariate regression and the least absolute shrinkage and selection operator (LASSO) Cox regression were used to construct a prognostic signature. R software was utilized to analyze the expression levels and prognostic values of genes in ccRCC. A total of 19 glutamine metabolic genes (GMGs) were screened out for differential expression analysis of normal and ccRCC tissues. Based on survival-related GMGs, two glutamine metabolic clusters with different clinical and transcriptomic characteristics were identified. Patients in cluster B exhibited worse survivals, higher immune infiltration scores, more significant immunosuppressive cell infiltration, higher expression levels of immune checkpoints, and more enriched oncogenic pathways. Glutamine metabolic index (GMI) was constructed according to the GMGs and survival data. In addition, the expression levels of GMGs were associated with immune cell infiltration and immune checkpoints in the TME of ccRCC. Among the GMGs, PYCR1 was the most powerful regulator of immune TME. Our analysis revealed higher-level glutamine metabolism in ccRCC patients with a worse prognosis. The GMI could predict the prognosis of ccRCC patients with a high accuracy. GMGs, such as PYCR1, may be exploited to design novel immunotherapies for ccRCC.
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Background: Renal clear cell cancer (ccRCC) is one of the most common cancers in humans. Thus, we aimed to construct a risk model to predict the prognosis of ccRCC effectively. Methods: We downloaded RNA sequencing (RNA-seq) data and clinical information of 539 kidney renal clear cell carcinoma (KIRC) patients and 72 normal humans from The Cancer Genome Atlas (TCGA) database and divided the data into training and testing groups randomly. Pyroptosis-related lncRNAs (PRLs) were obtained through Pearson correlation between pyroptosis genes and all lncRNAs (p < 0.05, coeff > 0.3). Univariate and multivariate Cox regression analyses were then performed to select suitable lncRNAs. Next, a novel signature was constructed and evaluated by survival analysis and ROC analysis. The same observation applies to the testing group to validate the value of the signature. By gene set enrichment analysis (GSEA), we predicted the underlying signaling pathway. Furthermore, we calculated immune cell infiltration, immune checkpoint, the T-cell receptor/B-cell receptor (TCR/BCR), SNV, and Tumor Immune Dysfunction and Exclusion (TIDE) scores in TCGA database. We also validated our model with an immunotherapy cohort. Finally, the expression of PRLs was validated by quantitative PCR (qPCR). Results: We constructed a prognostic signature composed of six key lncRNAs (U62317.1, MIR193BHG, LINC02027, AC121338.2, AC005785.1, AC156455.1), which significantly predict different overall survival (OS) rates. The efficiency was demonstrated using the receiver operating characteristic (ROC) curve. The signature was observed to be an independent prognostic factor in cohorts. In addition, we found the PRLs promote the tumor progression via immune-related pathways revealed in GSEA. Furthermore, the TCR, BCR, and SNV data were retrieved to screen immune features, and immune cell scores were calculated to measure the effect of the immune microenvironment on the risk model, indicating that high- and low-risk scores have different immune statuses. The TIDE algorithm was then used to predict the immune checkpoint blockade (ICB) response of our model, and subclass mapping was used to verify our model in another immunotherapy cohort data. Finally, qPCR validates the PRLs in cell lines. Conclusion: This study provided a new risk model to evaluate ccRCC and may be pyroptosis-related therapeutic targets in the clinic.
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BACKGROUND: Prostate cancer (PCa) is the most frequently diagnosed malignancy in men, and its mechanism remains poorly understood. Therefore, it is urgent to discover potential novel diagnostic biomarkers and therapeutic targets that can potentially facilitate the development of efficient anticancer strategies. METHODS: A series of functional in vitro and in vivo experiments were conducted to evaluate the biological behaviors of PCa cells. RNA pulldown, Western blot, luciferase reporter, immunohistochemistry and chromatin immunoprecipitation assays were applied to dissect the detailed underlying mechanisms. High-throughput sequencing was performed to screen for differentially expressed circRNAs in PCa and adjacent normal tissues. RESULTS: Upregulation of protein arginine methyltransferase 5 (PRMT5) is associated with poor progression-free survival and the activation of multiple signaling pathways in PCa. PRMT5 inhibits the transcription of CAMK2N1 by depositing the repressive histone marks H4R3me2s and H3R8me2s on the proximal promoter region of CAMK2N1, and results in malignant progression of PCa both in vitro and in vivo. Moreover, the expression of circSPON2, a candidate circRNA in PCa tissues identified by RNA-seq, was found to be associated with poor clinical outcomes in PCa patients. Further results showed that circSPON2 induced PCa cell proliferation and migration, and that the circSPON2-induced effects were counteracted by miR-331-3p. Particularly, circSPON2 acted as a competitive endogenous RNA (ceRNA) of miR-331-3p to attenuate the repressive effects of miR-331-3p on its downstream target PRMT5. CONCLUSIONS: Our findings showed that the epigenetic regulator PRMT5 aggravates PCa progression by inhibiting the transcription of CAMK2N1 and is modulated by the circSPON2/miR-331-3p axis, which may serve as a potential therapeutic target for patients with aggressive PCa.
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MicroRNAs , Neoplasias da Próstata , Linhagem Celular Tumoral , Epigênese Genética , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteínas/metabolismo , RNA Circular/genéticaRESUMO
Background: Adipogenic transdifferentiation was an important carcinogenic factor in various tumors, while studies on its role in clear cell renal cell carcinoma (ccRCC) were still relatively few. This study aimed to investigate its prognostic value and mechanism of action in ccRCC. Methods: Gene expression profiles and clinical data of ccRCC patients were obtained from The Cancer Genome Atlas database. Nonnegative matrix factorization was used for clustering. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were used to analyze the pathways and biological process activities. single-sample GSEA (ssGSEA) was utilized to quantify the relative abundance of each immune cell. Tumor Immune Estimation Resource (TIMER) was used to evaluate the proportion of various immune infiltrating cells across diverse cancer types. Real-Time PCR was performed to examine the gene expression. R software was utilized to analyze the expression and prognostic role of genes in ccRCC. Results: A total of 49 adipose-related genes (ARGs) were screened for differential expression between normal and ccRCC tissues. Based on differentially expressed ARGs, patients with ccRCC were divided into two adipose subtypes with different clinical, molecular, and pathway characteristics. Patients in cluster A exhibited more advanced pathological stages, higher expressions of RARRES2 and immune checkpoint genes, higher immune infiltration scores, and less nutrient metabolism pathways. Adipose differentiation index (ADI) was constructed according to the above ARGs and survival data, and its robustness and accuracy was validated in different cohorts. In addition, it was found that the expression of ARGs was associated with immune cell infiltration and immune checkpoint in ccRCC, among which GBP2 was thought to be the most relevant gene to the tumor immune microenvironment and play a potential role in carcinogenesis and invasion of tumor cells. Conclusion: Our analysis revealed the consistency of higher adipogenic transdifferentiation of tumor cells with worse clinical outcomes in ccRCC. The 16-mRNA signature could predict the prognosis of ccRCC patients with high accuracy. ARGs such as GBP2 might shed light on the development of novel biomarkers and immunotherapies of ccRCC.
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Background: Long non-coding RNAs (lncRNAs) are now under discussion as novel promising biomarkers for clear cell renal cell carcinoma (ccRCC). However, the role of genomic instability-associated lncRNA signatures in tumors has not been thoroughly uncovered. The purpose of our study is to probe the role of genomic instability-derived lncRNA signature (GILncSig) and to further investigate the mechanism of genomic instability-mediated ccRCC progression. Methods: The transcriptome data and somatic mutation profiles of ccRCC as well as clinical characteristics used in this study were obtained from The Cancer Genome Atlas database and Gene Expression Omnibus database. Lasso regression analysis was performed to construct the GILncSig. Gene set enrichment analysis (GSEA) was performed to elucidate the biological functions and relative pathways. CIBERSORT and EPIC algorithm were applied to calculate the proportion of immune cells in ccRCC. ESTIMATE algorithm was utilized to compute the immune microenvironment scores. Results: In total, 148 novel genomic instability-derived lncRNAs in ccRCC were identified. Immediately, on the basis of univariate cox analysis and lasso analysis, a GILncSig was appraised, through which the patients were allocated into High-Risk and Low-Risk groups with significantly different characteristics and prognoses. In addition, we confirmed that the somatic mutation count, tumor mutation burden, and the expression of UBQLN4, which were ascertainably associated with genomic instability, were significantly correlated with the GILncSig, indicating its reliability as a measurement of the genomic instability. Furthermore, the efficiency of GILncSig in prognostic aspects was better than the single mutation gene in ccRCC. In addition, MNX1-AS1 was defined to be a potential biomarker characterized by strong correlation with clinical features. Moreover, GSEA results indicated that the IL6/JAK/STAT3/SIGNALING pathway could be considered as a potential mechanism of genomic instability to influence tumor progression. Besides, the immune microenvironment showed significant differences between the GS-like group and the GU-like group, which was specifically manifested as high expression of CTLA4, GITR, TNFSF14, and regulatory T cells (Tregs) as well as low expression of endothelial cells (ECs) in the GU-like group. Finally, the prognostic value and clinical relevance of GILncSig were verified in GEO datasets and other urinary tumors in TCGA dataset. Conclusion: In conclusion, our study provided a new perspective for the role of lncRNAs in genomic instability and revealed that genomic instability may mediate tumor progression by affecting immunity. Besides, MNX1-AS1 played critical roles in promoting the progression of ccRCC, which may be a potential therapeutic target. What is more, the immune atlas of genomic instability was characterized by high expression of CTLA4, GITR, TNFSF14, and Tregs, and low expression of ECs.
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BACKGROUND: Considerable evidence has indicated an association between the immune microenvironment and clinical outcome in ccRCC. The purpose of this study is to extensively figure out the influence of immune-related genes of tumors on the prognosis of patients with ccRCC. METHODS: Files containing 2498 immune-related genes were obtained from the Immunology Database and Analysis Portal (ImmPort), and the transcriptome data and clinical information relevant to patients with ccRCC were identified and downloaded from the TCGA data-base. Univariate and multivariate Cox regression analyses were used to screen out prognostic immune genes. The immune risk score model was established in light of the regression coefficient between survival and hub immune-related genes. We eventually set up a nomogram for the prediction of the overall survival for ccRCC. Kaplan-Meier (K-M) and ROC curve was used in evaluating the value of the predictive risk model. A P value of < 0.05 indicated statistically significant differences throughout data analysis. RESULTS: Via differential analysis, we found that 556 immune-related genes were expressed differentially between tumor and normal tissues (p < 0. 05). The analysis of univariate Cox regression exhibited that there was a statistical correlation between 43 immune genes and survival risk in patients with ccRCC (p < 0.05). Through Lasso-Cox regression analysis, we established an immune genetic risk scoring model based on 18 immune-related genes. The high-risk group showed a bad prognosis in K-M analysis. (p < 0.001). ROC curve showed that it was reliable of the immune risk score model to predict survival risk (5 year over survival, AUC = 0.802). The model indicated satisfactory AUC and survival correlation in the validation data set (5 year OS, Area Under Curve = 0.705, p < 0.05). From Multivariate regression analysis, the immune-risk score model plays an isolated role in the prediction of the prognosis of ccRCC. Under multivariate-Cox regression analysis, we set up a nomogram for comprehensive prediction of ccRCC patients' survival rate. At last, it was identified that 18 immune-related genes and risk scores were not only tremendously related to clinical prognosis but also contained in a variety of carcinogenic pathways. CONCLUSION: In general, tumor immune-related genes play essential roles in ccRCC development and progression. Our research established an unequal 18-immune gene risk index to predict the prognosis of ccRCC visually. This index was found to be an independent predictive factor for ccRCC.
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Carcinoma de Células Renais/imunologia , Perfilação da Expressão Gênica/métodos , Neoplasias Renais/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Objective: M6A RNA modification is closely associated with tumor genesis and progression of several malignancies; however, its role in prostate cancer (PCa) remains poorly understood. Materials and methods: Expression data and corresponding clinicopathologic information were available freely from the Cancer Genome Atlas (TCGA) dataset. We compared the expression level of m6A RNA methylation regulators in PCa with different clinicopathologic characteristics and identified subgroups based on their expressions with consensus clustering. To build the signature and assess its prognostic value, several methods were used for the analysis, including univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, time-dependent receiver operating curve (ROC), and Kaplan-Meier (KM) survival analysis. Results: Most of the m6A RNA methylation regulators were differentially expressed not only between normal and tumor tissue but also among PCa stratified by different clinicopathologic characteristics. There were obvious differences between two clusters, cluster 1 and 2, regarding clinicopathologic features, and the recurrence-free survival (RFS) in cluster 2 was significantly worse than cluster 1. We developed an eleven-gene signature which exhibited a high prognostic value and was able to independently predict RFS. Moreover, a nomogram which integrated clinical information and the gene signature was capable of distinguishing high-risk recurrent patients. Conclusion: These methylation regulators are correlated to clinicopathologic characteristics in PCa and a prognostic model using m6A methylation-related genes is constructed and of high predictive value for recurrence after RP.
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Extensive research has revealed that the score derived from the Gleason grading system plays a pivotal role in predicting prostate cancer (PCa) progression. However, the underlying involvement of Gleason-related genes in PCa requires further investigation. This study aimed to identify Gleason-related genes with the potential to guide PCa therapy and future research. Differentially expressed genes (DEGs) were identified by comparing PCa tissues with high or low Gleason scores using the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. R v3.6.1, SPSS v23, and ImageJ software were used for all analyses. An effective recurrence-free survival (RFS) predictive model based on seven Gleason-related genes was established and validated (TCGA, AUC = 0.803; five years, AUC = 0.740; three years, AUC = 0.722; one year, AUC = 0.711; GSE46602, AUC = 0.766; five years, AUC = 0.808; three years, AUC = 0.723; one year, AUC = 0.656; GSE116918, AUC = 0.788; five years, AUC = 0.704; three years, AUC = 0.693; one year, AUC = 0.996). Calibration and nomogram plots were conducted. Weighted correlation network analysis (WGCNA) was used, and COL5A2 was selected for further analysis. The results from in vitro experiments demonstrated that COL5A2 was upregulated in PCa with high Gleason scores. The knockdown of COL5A2 inhibited cell proliferation and invasion in PC-3 and LNCaP cell lines. Meanwhile, COL5A2 displayed a strong association with immune infiltration, which might be an underlying immunotherapy target for PCa. We successfully established a robust RFS predictive model. The findings from this study indicated that COL5A2 could promote cell proliferation and invasion in PCa.
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Increasing evidence has indicated a close association between immune infiltration in cancer and clinical outcomes. However, related research in thyroid cancer is still deficient. Our research comprehensively investigated the immune infiltration of thyroid cancer. Data derived from TCGA and GEO databases were analyzed by the CIBERSORT, ESTIMATE, and EPIC algorithms. The CIBERSORT algorithm calculates the proportions of 22 types of immune cells. ESTIMATE algorithm calculates a stromal score to represent all stromal cells in cancer. The EPIC algorithm calculates the proportions of cancer-associated fibroblasts (CAFs) and endothelial cells (ECs), which are the main components of stromal cells. We analyzed the correlation of immune infiltration with clinical characteristics and outcomes of patients. We determined that the infiltration of CD8+ T cells improved the survival of thyroid cancer patients. Overexpression of immune checkpoints was closely related to the development of thyroid cancer. In general, stromal cells were associated with the progression of thyroid cancer. Interestingly, CAFs and ECs had opposite roles in this process. In addition, the BRAFV600E mutation was related to the upregulation of immune checkpoints and CAFs and the downregulation of CD8+ T cells and ECs. Finally, we constructed an immune risk score model to predict the prognosis and development of thyroid cancer. Our research demonstrated a comprehensive panorama of immune infiltration in thyroid cancer, which may provide potential value for immunotherapy.
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Câncer Papilífero da Tireoide/imunologia , Adulto , Feminino , Humanos , Masculino , Fatores de Risco , Transfecção , Microambiente TumoralRESUMO
BACKGROUND: It is well known that chronic inflammation can promote the occurrence and progression of cancer. As a type of proinflammatory death, pyroptosis can recast a suitable microenvironment to promote tumor growth. However, the potential role of pyroptosis in clear cell renal cell carcinoma (ccRCC) remains unclear. METHODS: The transcriptome expression profile and mutation profile data of ccRCC with clinical characteristics included in this study were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Consensus clustering was used for clustering. Gene set enrichment analysis (GSEA) analysis were applied to evaluate the biological mechanisms. Single sample gene set enrichment analysis (ssGSEA) was applied for evaluating the proportion of various immune infiltrating cells. The ESTIMATE algorithm was involved to compute the immune microenvironment scores. RESULTS: Among the 17 pyroptosis regulators, a total of 15 pyroptosis regulators were differential expressed between tumor and normal tissues, in which 12 of them emerged strong correlations with prognoses. According to the pyroptosis components, the ccRCC patients were divided into four pyroptosis subtypes with different clinical, molecular, and pathway characteristics. Compared with other clusters, cluster B showed the pyroptosis heat phenotype, while cluster D represented the pyroptosis cold phenotype with poor overall survival. In addition, we performed principal component analysis (PCA) on the differential genes between clusters to construct the pyroptosis index. Furthermore, the pyroptosis index was significantly correlated with survival in different tumor mutation statuses and different grades and stages. Besides, the expression of pyroptosis-related regulators was related to the infiltration of immune cells and the expression of immune checkpoints, among which AIM2 was considered as the most significant immune-related pyroptosis regulator. Ultimately, we found that AIM2 was related to the immune activation pathway and was significantly overexpressed in tumor tissues. CONCLUSION: This study revealed that pyroptosis regulators and pyroptosis index played an important role in the development and prognoses of ccRCC. Moreover, AIM2 can be used as a predictor of the response of immunotherapy. Assessing the pyroptosis patterns may help evaluate the tumor status and guide immunotherapy strategies.
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Perfluorooctanoic acid (PFOA) is an artificial organic substance widely used for decades, which seriously threatens human health. This study aimed to identify human-relevant correlates between PFOA exposure and the male rodent reproductive system. We performed a systematic literature review of the relevant literature of PubMed, Cochrane Library databases, Web of Science and Embase from the establishment to April 2020. Studies included the effects of PFOA on the reproductive system of male rodents. The meta-analysis was performed on the basis of the following points: level of testosterone and estradiol in serum, development of reproductive organs, pathological changes of reproduction organs and parameters of semen. A series of 16 studies was enrolled in this study. The standard mean difference (SMD) for PFOA-related reproductive toxicity was summarised as -0.39 (95% confidence interval [CI]: 0.71, -0.07). The lower serum testosterone levels, decreased absolute testicular and epididymal weights, higher serum estradiol levels, elevated relative testicular and seminal vesicle weights and increased incidence of Leydig cell adenoma and percentage of abnormal sperm were observed in the exposed group compared with the control group. However, no statistical difference was found in the day of preputial separation of pups and percentage of motile sperm. In conclusion, PFOA exposure heightens the reproductive system damage in male rodents. However, many studies included in the review did not identify mechanisms by which PFOA induces changes to the male reproductive system, which is an area for additional study.