ABSTRACT
BACKGROUND/AIM: Autophagy and immunity play important roles in the growth of malignant tumors and are promising targets for tumor therapy. This study was conducted to identify differentially expressed immune genes related to autophagy in Wilms' tumor (WT) and analyze their correlation with the disease prognosis. MATERIALS AND METHODS: The public data of WT and normal kidney tissues were downloaded from TCGA, ImmPort, and GeneCards databases to obtain differentially expressed immune genes associated with autophagy. Survival analysis, ROC curve, and clinical relevance filtering were used to screen the key gene plasminogen activator urokinase (PLAU). The univariable and multivariable Cox regression model analyses were used to analyze the prognostic factors of overall survival (OS) in patients with WT. Then, GO enrichment, KEGG pathway analysis and GSEA were used to enrich and analyze differentially expressed genes. The relationship between PLAU gene expression and tumor microenvironment and infiltration of immune cells was analyzed, as well as between the expression of PLAU and epigenetic modifications. RESULTS: PLAU gene expression was associated with survival and prognosis in WT patients and was an independent prognostic indicator of OS in patients. The GO, KEGG, and GSEA analysis results suggested that PLAU may be involved in RNA transcription and epithelial cell migration. High expression of PLAU was also associated with increased immune cell infiltration and a higher presence of antitumor immune cells. The low expression of PLAU in WT was related to DNA methylation and may be also co-regulated by miR-342-3p. CONCLUSION: PLAU can be used as an independent prognostic biomarker for WT. Low expression of PLAU is associated with poor prognosis in WT patients. Evidence on the prognostic value of PLAU gene and the pathways that may be associated with its expression is invaluable for the development of new therapies for WT.
Subject(s)
Biomarkers, Tumor , Computational Biology , Gene Expression Regulation, Neoplastic , Kidney Neoplasms , Wilms Tumor , Humans , Prognosis , Computational Biology/methods , Wilms Tumor/genetics , Wilms Tumor/pathology , Wilms Tumor/mortality , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/mortality , Kidney Neoplasms/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Tumor Microenvironment/genetics , Gene Expression Profiling , Female , Male , Membrane ProteinsABSTRACT
BACKGROUND/AIM: Wilms' tumors are pediatric renal tumors that generally have a good prognosis and outcomes. Viral illnesses have been linked to development of neoplasms and should be considered as a factor that could modulate overall survival. MATERIALS AND METHODS: We considered recently developed adaptive immune receptor, genomics and bioinformatics approaches to assess the potential impact of cytomegalovirus (CMV) infections in Wilms' tumor. RESULTS: T-cell receptor (TCR) complementarity determining region-3 (CDR3) amino acid sequences from Wilms' tumor specimens represented by the Therapeutically Applicable Research to Generate Effective Treatments dataset were compared with known anti-CMV TCR CDR3s, indicating that cases representing the anti-CMV TCR CDR3s had worse outcomes. Then, a chemical complementarity scoring approach for the Wilms' tumor, TCR CDR3s and a series of CMV antigens further indicated that cases representing a higher chemical complementarity to the CMV antigens had worse outcomes. CONCLUSION: Overall, we present a potentially novel method to assess CMV infections and identify patients who could benefit from therapies that address such infections.
Subject(s)
Complementarity Determining Regions , Cytomegalovirus , Kidney Neoplasms , Receptors, Antigen, T-Cell , Wilms Tumor , Humans , Wilms Tumor/immunology , Wilms Tumor/genetics , Complementarity Determining Regions/genetics , Complementarity Determining Regions/immunology , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Kidney Neoplasms/immunology , Kidney Neoplasms/genetics , Cytomegalovirus/immunology , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/virology , Prognosis , Epitopes/immunologyABSTRACT
BACKGROUND: The potential involvement of circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification in the progression of Wilms tumor (WT) has not been fully elucidated. This study investigates the regulatory mechanisms and clinical significance of m6A-modified circMARK2 and its role in WT progression. METHODS: We identified dysregulated circRNAs through deep sequencing and validated their expression by qRT-PCR in WT tissues. The biological functions of circMARK2 were assessed using clone formation, transwell migration, and orthotopic animal models. To dissect the underlying mechanisms, we employed RNA immunoprecipitation, RNA pull-down, dual-luciferase reporter assays, Western blotting, and immunofluorescence and immunohistochemical staining. RESULTS: CircMARK2, upregulated in WT tissues, was found to be m6A-modified and promoted cytoplasmic export. It facilitated WT progression by stabilizing LIN28B mRNA through the circMARK2/IGF2BP2 interaction. In vitro and in vivo studies demonstrated that circMARK2 enhances the malignant behavior of WT cells. Clinically, higher circMARK2 levels in tumor tissues of WT patients were linked to increased tumor aggressiveness and reduced survival rates. CONCLUSIONS: Our study provides the first comprehensive evidence that m6A-modified circMARK2 contributes to WT progression by enhancing LIN28B mRNA stability, promoting cellular aggressiveness. CircMARK2 emerges as a potential biomarker for prognosis and a promising target for therapeutic intervention in WT, underscoring the clinical relevance of m6A modification in pediatric renal cancer.
Subject(s)
Adenosine , Disease Progression , RNA, Circular , RNA-Binding Proteins , Wilms Tumor , Animals , Female , Humans , Male , Mice , Adenosine/analogs & derivatives , Adenosine/metabolism , Cell Line, Tumor , Cytoplasm/metabolism , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Prognosis , RNA, Circular/genetics , RNA, Circular/metabolism , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Wilms Tumor/metabolism , Wilms Tumor/genetics , Wilms Tumor/pathologyABSTRACT
How disruptions to normal cell differentiation link to tumorigenesis remains incompletely understood. Wilms tumor, an embryonal tumor associated with disrupted organogenesis, often harbors mutations in epigenetic regulators, but their role in kidney development remains unexplored. Here, we show at single-cell resolution that a Wilms tumor-associated mutation in the histone acetylation reader ENL disrupts kidney differentiation in mice by rewiring the gene regulatory landscape. Mutant ENL promotes nephron progenitor commitment while restricting their differentiation by dysregulating transcription factors such as Hox clusters. It also induces abnormal progenitors that lose kidney-associated chromatin identity. Furthermore, mutant ENL alters the transcriptome and chromatin accessibility of stromal progenitors, resulting in hyperactivation of Wnt signaling. The impacts of mutant ENL on both nephron and stroma lineages lead to profound kidney developmental defects and postnatal mortality in mice. Notably, a small molecule inhibiting mutant ENL's histone acetylation binding activity largely reverses these defects. This study provides insights into how mutations in epigenetic regulators disrupt kidney development and suggests a potential therapeutic approach.
Subject(s)
Cell Differentiation , Kidney , Mutation , Single-Cell Analysis , Animals , Mice , Kidney/metabolism , Kidney/pathology , Cell Differentiation/genetics , Gene Expression Regulation, Developmental , Chromatin/metabolism , Epigenesis, Genetic , Wilms Tumor/genetics , Wilms Tumor/pathology , Wilms Tumor/metabolism , Histones/metabolism , Acetylation , Humans , Organogenesis/genetics , Wnt Signaling Pathway/genetics , Nephrons/metabolism , Nephrons/pathology , Nephrons/embryology , Transcriptome/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Female , Male , MultiomicsABSTRACT
BACKGROUND: Wilms tumor (WT) is the most common pediatric embryonal tumor. Improving patient outcomes requires advances in understanding and targeting the multiple genes and cellular control pathways, but its pathogenesis is currently not well-researched. We aimed to identify the potential molecular biological mechanism of WT and develop new prognostic markers and molecular targets by comparing gene expression profiles of Wilms tumors and fetal normal kidneys. METHODS: Differential gene expression analysis was performed on Wilms tumor transcriptomic data from the GEO and TARGET databases. For biological functional analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were utilized. Out of 24 hub genes identified, nine were found to be prognostic-related through univariate Cox regression analysis. These nine genes underwent LASSO regression analysis to enhance the predictive capability of the model. The key hub genes were validated in the GSE73209 datasets, and cell function experiments were conducted to identify the genes' functions in WiT-49 cells. RESULTS: The enrichment analysis revealed that DEGs were significantly involved in the regulation of angiogenesis and regulation of cell differentiation. 24 DEGs were identified through PPI networks and the MCODE algorithm, and 9 of 24 genes were related to WT patients' prognosis. EMCN and CCNA1 were identified as key hub genes, and related to the progression of WT. Functionally, over-expression of EMCN and CCNA1 knockdown inhibited cell viability, proliferation, migration, and invasion of Wilms tumor cells. CONCLUSIONS: EMCN and CCNA1 were identified as key prognostic markers in Wilms tumor, suggesting their potential as therapeutic targets. Differential gene expression and enrichment analyses indicate significant roles in angiogenesis and cell differentiation.
Subject(s)
Biomarkers, Tumor , Computational Biology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Kidney Neoplasms , Wilms Tumor , Wilms Tumor/genetics , Wilms Tumor/pathology , Humans , Computational Biology/methods , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Biomarkers, Tumor/genetics , Prognosis , Gene Regulatory Networks , Transcriptome , Cell Proliferation/genetics , Protein Interaction Maps/genetics , Gene Ontology , Cell Line, TumorABSTRACT
BACKGROUND: Wilms tumor is the most prevalent embryonal kidney malignancy in children worldwide. Previous genome-wide association study (GWAS) identified that LIM domain only 1 (LMO1) gene polymorphisms affected the susceptibility to develop certain tumor types. Apart from LMO1, the LMO gene family members also include LMO2-4, each of which has oncogenic potential. METHODS: We conducted this five-center caseâcontrol study to assess the correlations between single nucleotide polymorphisms in LMO family genes and Wilms tumor susceptibility. Odds ratios and 95% confidence intervals were calculated to evaluate the strength of the association. RESULTS: We found LMO1 rs2168101 G > T and rs11603024 C > T as well as LMO2 rs7933499 G > A were significantly associated with Wilms tumor risk. Stratified analysis demonstrated a protective role of rs2168101 GT/TT genotypes against Wilms tumor in the subgroups of age ≤ 18 months, males and clinical stages I/II compared to the rs2168101 GG genotype. Nevertheless, carriers with the rs11603024 TT genotype were more likely to have an increased risk of Wilms tumor than those with rs11603024 CC/CT genotypes in age > 18 months. And the rs11603024 was identified as a protective polymorphism for reducing the risk of Wilms tumor in the sex- and gender- subgroup. Likewise, carriers with the rs7933499 GA/AA genotypes were at significantly elevated risk of Wilms tumor in age ≤ 18 months and clinical stages I/II. CONCLUSION: Overall, our study identified the importance of LMO family gene polymorphisms on Wilms tumor susceptibility in Chinese children. Further investigations are needed to validate our conclusions.
Subject(s)
Genetic Predisposition to Disease , Kidney Neoplasms , LIM Domain Proteins , Polymorphism, Single Nucleotide , Wilms Tumor , Child , Child, Preschool , Female , Humans , Infant , Male , Adaptor Proteins, Signal Transducing/genetics , Case-Control Studies , China/epidemiology , DNA-Binding Proteins/genetics , East Asian People/genetics , Genotype , Kidney Neoplasms/genetics , LIM Domain Proteins/genetics , Proto-Oncogene Proteins/genetics , Transcription Factors/genetics , Wilms Tumor/genetics , Multigene FamilyABSTRACT
OBJECTIVE: To identify the key genes differentially expressed in Wilms tumor and analyze their potential impacts on prognosis and immune responses of the patients. METHODS: High-throughput RNA sequencing was used to identify the differentially expressed mRNAs in clinical samples of Wilms tumor and paired normal tissues, and their biological functions were analyzed using GO, KEGG and GSEA enrichment analyses. The hub genes were identified using STRING database, based on which a prognostic model was constructed using LASSO regression. The mutations of the key hub genes were analyzed and their impacts on immunotherapy efficacy was predicted using the cBioPortal platform. RT-qPCR was used to verify the differential expressions of the key hub genes in Wilms tumor. RESULTS: Of the 1612 differentially expressed genes identified in Wilms tumor, 1030 were up-regulated and 582 were down-regulated, involving mainly cell cycle processes and immune responses. Ten hub genes were identified, among which 4 genes (TP53, MED1, CCNB1 and EGF) were closely related to the survival of children with Wilms tumor. A 3-gene prognostic signature was constructed through LASSO regression analysis, and the patients stratified into with high- and low-risk groups based on this signature had significantly different survival outcomes (HR=1.814, log-rank P=0.002). The AUCs of the 3-, 5- and 7-year survival ROC curves of this model were all greater than 0.7. The overall mutations in the key hub genes or the individual mutations in TP53/CCNB1 were strongly correlated with a lower survival rates, and a high TP53 expression was correlated with a poor immunotherapy efficacy. RT-qPCR confirmed that the key hub genes had significant differential expressions in Wilms tumor tissues and cells. CONCLUSION: TP53 gene plays an important role in the Wilms tumor and may potentially serve as a new immunotherapeutic biomarker as well as a therapeutic target.
Subject(s)
Kidney Neoplasms , Wilms Tumor , Humans , Wilms Tumor/genetics , High-Throughput Nucleotide Sequencing , Prognosis , Kidney Neoplasms/genetics , Genes, Wilms Tumor , Tumor MicroenvironmentABSTRACT
Wilms tumor, the most common pediatric kidney cancer, resembles embryonic renal progenitors. Currently, there are no ways to therapeutically target Wilms tumor driver mutations, such as in the microRNA processing gene DROSHA. In this study, we used a "multiomics" approach to define the effects of DROSHA mutation in Wilms tumor. We categorized Wilms tumor mutations into four mutational subclasses with unique transcriptional effects: microRNA processing, MYCN activation, chromatin remodeling, and kidney developmental factors. In particular, we find that DROSHA mutations are correlated with de-repressing microRNA target genes that regulate differentiation and proliferation and a self-renewing, mesenchymal state. We model these findings by inhibiting DROSHA expression in a Wilms tumor cell line, which led to upregulation of the cell cycle regulator cyclin D2 (CCND2). Furthermore, we observed that DROSHA mutations in Wilms tumor and DROSHA silencing in vitro were associated with a mesenchymal state with aberrations in redox metabolism. Accordingly, we demonstrate that Wilms tumor cells lacking microRNAs are sensitized to ferroptotic cell death through inhibition of glutathione peroxidase 4, the enzyme that detoxifies lipid peroxides. Implications: This study reveals genotype-transcriptome relationships in Wilms tumor and points to ferroptosis as a potentially therapeutic vulnerability in one subset of Wilms tumor.
Subject(s)
Kidney Neoplasms , Ribonuclease III , Wilms Tumor , Humans , Wilms Tumor/genetics , Wilms Tumor/pathology , Wilms Tumor/metabolism , Ribonuclease III/genetics , Ribonuclease III/metabolism , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Mutation , MicroRNAs/genetics , Cell Line, TumorABSTRACT
BACKGROUND: Wilms' tumor (WT) is the most common renal tumor in childhood. Pyroptosis, a type of inflammation-characterized and immune-related programmed cell death, has been extensively studied in multiple tumors. In the current study, we aim to construct a pyroptosis-related gene signature for predicting the prognosis of Wilms' tumor. METHODS: We acquired RNA-seq data from TARGET kidney tumor projects for constructing a gene signature, and snRNA-seq data from GEO database for validating signature-constructing genes. Pyroptosis-related genes (PRGs) were collected from three online databases. We constructed the gene signature by Lasso Cox regression and then established a nomogram. Underlying mechanisms by which gene signature is related to overall survival states of patients were explored by immune cell infiltration analysis, differential expression analysis, and functional enrichment analysis. RESULTS: A pyroptosis-related gene signature was constructed with 14 PRGs, which has a moderate to high predicting capacity with 1-, 3-, and 5-year area under the curve (AUC) values of 0.78, 0.80, and 0.83, respectively. A prognosis-predicting nomogram was established by gender, stage, and risk score. Tumor-infiltrating immune cells were quantified by seven algorithms, and the expression of CD8( +) T cells, B cells, Th2 cells, dendritic cells, and type 2 macrophages are positively or negatively correlated with risk score. Two single nuclear RNA-seq samples of different histology were harnessed for validation. The distribution of signature genes was identified in various cell types. CONCLUSIONS: We have established a pyroptosis-related 14-gene signature in WT. Moreover, the inherent roles of immune cells (CD8( +) T cells, B cells, Th2 cells, dendritic cells, and type 2 macrophages), functions of differentially expressed genes (tissue/organ development and intercellular communication), and status of signaling pathways (proteoglycans in cancer, signaling pathways regulating pluripotent of stem cells, and Wnt signaling pathway) have been elucidated, which might be employed as therapeutic targets in the future.
Subject(s)
Kidney Neoplasms , Pyroptosis , Wilms Tumor , Humans , Pyroptosis/genetics , Wilms Tumor/genetics , Wilms Tumor/immunology , Kidney Neoplasms/genetics , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Prognosis , Nomograms , Lymphocytes, Tumor-Infiltrating/immunology , Transcriptome , Female , MaleABSTRACT
The significant heterogeneity of Wilms' tumors between different patients is thought to arise from genetic and epigenetic distortions that occur during various stages of fetal kidney development in a way that is poorly understood. To address this, we characterized the heterogeneity of alternative mRNA splicing in Wilms' tumors using a publicly available RNAseq dataset of high-risk Wilms' tumors and normal kidney samples. Through Pareto task inference and cell deconvolution, we found that the tumors and normal kidney samples are organized according to progressive stages of kidney development within a triangle-shaped region in latent space, whose vertices, or "archetypes", resemble the cap mesenchyme, the nephrogenic stroma, and epithelial tubular structures of the fetal kidney. We identified a set of genes that are alternatively spliced between tumors located in different regions of latent space and found that many of these genes are associated with the epithelial-to-mesenchymal transition (EMT) and muscle development. Using motif enrichment analysis, we identified putative splicing regulators, some of which are associated with kidney development. Our findings provide new insights into the etiology of Wilms' tumors and suggest that specific splicing mechanisms in early stages of development may contribute to tumor development in different patients.
Subject(s)
Alternative Splicing , Epithelial-Mesenchymal Transition , Kidney Neoplasms , Wilms Tumor , Wilms Tumor/genetics , Wilms Tumor/pathology , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic , Kidney/metabolism , Kidney/pathologyABSTRACT
Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.
Subject(s)
Hydrazines , Kidney Neoplasms , Triazoles , Wilms Tumor , Humans , Exportin 1 Protein , Active Transport, Cell Nucleus , Karyopherins/genetics , Karyopherins/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Cell Line, Tumor , Apoptosis , Neoplasm Recurrence, Local , Doxorubicin/pharmacology , Wilms Tumor/drug therapy , Wilms Tumor/genetics , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , ATPases Associated with Diverse Cellular Activities/metabolism , Cell Cycle Proteins/metabolismABSTRACT
BACKGROUND: Wilms' tumour is the most prevalent abdominal malignancy in children. This study focused on the mechanism of the miR-590-3p/Dickkopf 1 (DKK1) axis in Wilms' tumour. METHODS: The mRNA levels of miR-590-3p and DKK1 in 49 pairs of Wilms' tumour pathological specimens and normal tissues were determined using real-time quantitative polymerase chain reaction (RT-qPCR). Wilms' tumour cells' invasion ability and proliferative ability were assessed using a Transwell assay and Cell Counting Kit-8 (CCK-8) assay, respectively. Dual-luciferase assay was performed to evaluate the potential relationship between miR-590-3p and DKK1 in Wilms tumour. Furthermore, a mouse transplanted tumour model was constructed to explore the function of miR-590-3p inhibitor on Wilms' tumour growth in vivo. RESULTS: DKK1 emerged as a target gene of miR-590-3p in Wilms' tumour. DKK1 expression was downregulated (p < 0.01), but miR-590-3p was overexpressed (p < 0.01) in Wilms' tumour tissues compared to normal tissues. miR-590-3p overexpression accelerated Wilms' tumour invasive ability and cell proliferation (p < 0.01). Additionally, DKK1 partially reversed miR-590-3p-induced proliferation (p < 0.05) and invasion ability (p < 0.01). Furthermore, downregulation of miR-590-3p restrained the growth rate of transplanted tumours in nude mice (p < 0.01). CONCLUSIONS: Through the regulation of DKK1, miR-590-3p accelerated the invasion and proliferation of Wilms' tumour. The study suggests that the miR-590-3p/DKK1 axis represents a novel mechanism in Wilms' tumour.
Subject(s)
Kidney Neoplasms , MicroRNAs , Wilms Tumor , Child , Humans , Mice , Animals , MicroRNAs/genetics , Mice, Nude , Cell Movement/genetics , Wilms Tumor/genetics , Wilms Tumor/metabolism , Wilms Tumor/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolismABSTRACT
Objective: To investigate the relationship between 1p/16q loss of heterozygosity (LOH) and 1p gain in Wilms tumor and their clinicopathologic characteristics and prognosis. Methods: A total of 175 Wilms tumor samples received from the Department of Pathology, Beijing Children's Hospital from September 2019 to August 2022 were retrospectively analyzed. The histopathologic type and presence of lymph node involvement were evaluated by two pathologists. The clinical data including patients'gender, age, tumor location, preoperative chemotherapy, and tumor stage were summarized. Fluorescence in situ hybridization (FISH) was done to detect 1p/16q LOH and 1p gain and their correlation with the clinicopathological features and prognosis were analyzed. Results: Among the 175 samples, 86 cases (49.1%) were male and 89 (50.9%) were female. The mean age was (3.5±2.9) years, and the median age was 2.6 years. There were 26 (14.9%) cases with 1p LOH, 28 (16.0%) cases with 16q LOH, 10 (5.7%) cases of LOH at both 1p and 16q, and 53 (30.3%) cases with 1q gain. 1q gain was significantly associated with 1p LOH (P<0.01) and 16q LOH (P<0.01). There were significant differences (P<0.01) between 1q gain, 1p LOH and 16q LOH among different age groups. The rate of 16q LOH in the high-risk histopathological subtype (50.0%) was significantly higher than that in the intermediate-risk subtype (13.6%, P<0.05). The frequency of 1q gain, 1p LOH, and 16q LOH in children with advanced clinical stages (â ¢ and â £) was significantly higher than that in children with early clinical stages (â and â ¡). 1q gain, 1p LOH, and 16q LOH showed no significant correlation with gender, unilateral or bilateral disease, chemotherapy, or lymph node metastasis. The progression-free survival (PFS) time for patients with 1q gain and 1p LOH was significantly shorter than those without these aberrations (P<0.05). Additionally, the PFS time of patients with 16q LOH was slightly shorter than those with normal 16q, although the difference was not statistically significant. Patients with stage â ¢ to â £ disease exhibiting 1q gain or 1p LOH had a significantly higher relative risk of recurrence, metastasis, and mortality. Conclusions: 1p/16q LOH and 1q gain are associated with age, high-risk histological type, and clinical stage in Wilms tumor. 1q gain and 1p LOH are significantly correlated with the prognosis of Wilms tumor.
Subject(s)
Kidney Neoplasms , Wilms Tumor , Child , Humans , Female , Male , Child, Preschool , Infant , In Situ Hybridization, Fluorescence , Retrospective Studies , Prognosis , Wilms Tumor/genetics , Chromosome Aberrations , Kidney Neoplasms/genetics , Loss of HeterozygosityABSTRACT
To explore the action and mechanism in which circular RNA (circRNA) mitofusin 2 (MFN2) repressed the malignant proliferation of Wilms tumor (WT) via modulating microRNA (miR)-372-3p/transforming growth factor-ß receptor type 2 (TGFBR2) axis. CircRNA MFN2 was distinctly elevated in the tissues and cells of WT patients, while miR-372-3p was silenced in the tissues and cells of WT. Test of TGFBR2, PCNA and Bax was implemented. Transfection with si-circRNA MFN2 or miR-372-3p-mimic restrained cancer cell advancement and the number of PCNA content was declined, while transfection with miR-372-3p-inhibitor was opposite, and PCNA content was augmented. MiR-372-3p-inhibitor turned around si-circRNA MFN2's therapeutic action after co-transfection with si-circRNA MFN2 + miR-372-3p-inhibitor. Ultimately, it was verified that circRNA MFN2 was negatively associated with miR-372-3p, which was negatively linked with TGFBR2, and circRNA MFN2 was positively associated with TGFBR2. To sum up, the results of this research illuminated circRNA MFN2 repressed WT's malignant proliferation via modulating miR-372-3p/TGFBR2 axis.
Subject(s)
MicroRNAs , RNA, Circular , Receptor, Transforming Growth Factor-beta Type II , Wilms Tumor , Humans , Cell Line, Tumor , Cell Proliferation/genetics , MicroRNAs/genetics , Proliferating Cell Nuclear Antigen , Receptor, Transforming Growth Factor-beta Type II/genetics , RNA, Circular/genetics , Transforming Growth Factors , Wilms Tumor/geneticsABSTRACT
BACKGROUND: Nephroblastoma, also more commonly known as Wilms tumor (WT), is a common childhood malignancy that connects tumorigenesis and organ development in the kidney. OBJECTIVE: The current study focused on the effect of lncRNA FTX in nephroblastoma. STUDY DESIGN: Expression of lncRNA FTX in nephroblastoma tissues and cells was determined. The expression location of lncRNA FTX was detected by FISH. The binding of lncRNA FTX and miR-215-5p with Ago2 was verified by RIP. Following gain- and loss-of-function approaches, the crucial role of lncRNA FTX and miR-215-5p in nephroblastoma cell functions was measured with the involvement of the PI3K/AKT pathway. RESULTS: LncRNA FTX was elevated and miR-215-5p was declined in nephroblastoma. Silencing of lncRNA FTX or mimic of miR-215-5p inhibited the malignant properties of nephroblastoma cells. LncRNA FTX was localized in the cytoplasm and might bind miR-215-5p. LncRNA FTX promoted the malignant features of nephroblastoma cells by inhibiting miR-215-5p through activating of the PI3K/AKT pathway. CONCLUSIONS: LncRNA FTX is capable of accelerating nephroblastoma development in vitro by reducing miR-215-5p through activating of the PI3K/AKT pathway, indicating LncRNA FTX may possibly a future target for the diagnosis and treatment of nephroblastoma. SUMMARY FIGURE.
Subject(s)
Disease Progression , Kidney Neoplasms , MicroRNAs , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , RNA, Long Noncoding , Wilms Tumor , Humans , Cell Proliferation , Gene Expression Regulation, Neoplastic , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Signal Transduction , Tumor Cells, Cultured , Wilms Tumor/genetics , Wilms Tumor/pathology , Wilms Tumor/metabolismABSTRACT
Historically, specific mutations in WT1 gene have been associated with distinct syndromes based on phenotypic characteristics, including Denys-Drash syndrome (DDS), Frasier syndrome (FS), Meacham syndrome, and WAGR syndrome. DDS is classically defined by the triad of steroid-resistant nephrotic syndrome (SRNS) onset in the first year of life, disorders of sex development (DSD), and a predisposition to Wilms tumor (WT). Currently, a paradigm shift acknowledges a diverse spectrum of presentations beyond traditional syndromic definitions. Consequently, the concept of WT1-related disorders becomes more precise. A genotype-phenotype correlation has been established, emphasizing that the location and type of WT1 mutations significantly influence the clinical presentation, the condition severity, and the chronology of patient manifestations. Individuals presenting with persistent proteinuria, with or without nephrotic syndrome, and varying degrees of kidney dysfunction accompanied by genital malformations should prompt suspicion of WT1 mutations. Recent genetic advances enable a more accurate estimation of malignancy risk in these patients, facilitating a conservative nephron-sparing surgery (NSS) approach in select cases, with a focus on preserving residual kidney function and delaying nephrectomies. Other key management strategies include kidney transplantation and addressing DSD and gonadoblastoma. In summary, recent genetic insights underscore the imperative to implement individualized, integrated, and multidisciplinary management strategies for WT1-related disorders. This approach is pivotal in optimizing patient outcomes and addressing the complexities associated with these diverse clinical manifestations.
Subject(s)
Denys-Drash Syndrome , Mutation , WT1 Proteins , Humans , Denys-Drash Syndrome/genetics , Denys-Drash Syndrome/diagnosis , Denys-Drash Syndrome/therapy , WT1 Proteins/genetics , Phenotype , Nephrotic Syndrome/genetics , Nephrotic Syndrome/diagnosis , Nephrotic Syndrome/therapy , Wilms Tumor/genetics , Wilms Tumor/therapy , Wilms Tumor/diagnosis , Frasier Syndrome/genetics , Frasier Syndrome/therapy , Frasier Syndrome/diagnosisABSTRACT
AIM: This study reports the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins subsequently diagnosed with Wilms tumour (WAGR syndrome). METHODS: Two monozygotic female twins were referred at age 2 months with bilateral corneal opacity. A diagnosis of Peters' anomaly associated to aniridia was made in both eyes of both twins. Physical examination and ultrasonography were carried out at 12 months of age to explore the possibility of WAGR-related anomalies, specifically Wilms tumour. DNA were isolated and subjected to whole exome sequencing. RESULTS: Peters' anomaly associated to aniridia in both eyes as well as bilateral Wilms tumour in both children were diagnosed. Exome analyses showed a large heterozygous deletion encompassing 6 648 473 bp in chromosome 11p13, using Integrative Genomics Viewer and AnnotSV software. CONCLUSION: WAGR syndrome is a rare contiguous gene deletion syndrome with a greater risk of developing Wilms tumour associated with Peters' anomaly and congenital aniridia. However, co-occurrence of both anomalies was rarely reported in twins, and never in both eyes of monozygotic twins. Here, we report the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins with WAGR syndrome.
Subject(s)
Aniridia , Corneal Opacity , Twins, Monozygotic , WAGR Syndrome , Wilms Tumor , Humans , Female , Twins, Monozygotic/genetics , WAGR Syndrome/genetics , Aniridia/genetics , Aniridia/complications , Wilms Tumor/genetics , Wilms Tumor/complications , Infant , Corneal Opacity/genetics , Anterior Eye Segment/abnormalities , Anterior Eye Segment/diagnostic imaging , Eye Abnormalities/genetics , Eye Abnormalities/diagnostic imaging , Eye Abnormalities/complications , Diseases in Twins/genetics , Kidney Neoplasms/genetics , Kidney Neoplasms/diagnostic imaging , Kidney Neoplasms/complicationsABSTRACT
BACKGROUND: Nephroblastoma, also known as Wilms' tumor (WT), is an embryonic malignant tumor and one of the most common malignant tumors in the abdominal region of children. The exact role and underlying mechanisms of aquaporin-1 (AQP1) in the occurrence and development of nephroblastoma remain unclear. METHODS: After overexpression of AQP1, cell proliferation was assessed using the CCK-8 proliferation assay and EdU staining. Flow cytometry was employed to assess cell apoptosis, and Western blotting (WB) analysis was conducted to validate the expression of relevant protein markers. mRNA sequencing (mRNA-Seq) was performed on WT cells overexpressing AQP1 to predict and characterize the associated mechanisms. Transmission electron microscopy was utilized to observe changes in the ultrastructure of WT cells undergoing apoptosis and pyroptosis following AQP1 overexpression. Functional in vivo validation was conducted through animal experiments. RESULTS: We validated that overexpression of AQP1 inhibited cell proliferation and promoted cell apoptosis and pyroptosis both in vitro and in vivo. mRNA-Seq analysis of WT cells with AQP1 overexpression suggested that these effects might be mediated through the inhibition of the JAK-STAT signaling pathway. Additionally, we discovered that overexpression of AQP1 activated the classical pyroptosis signaling pathway dependent on caspase-1, thereby promoting pyroptosis in WT. CONCLUSION: These findings highlight the important functional role of AQP1 in the pathobiology of nephroblastoma, providing novel insights into the development of this disease. Moreover, these results offer new perspectives on the potential therapeutic targeting of AQP1 as a treatment strategy for nephroblastoma.
Subject(s)
Aquaporin 1 , Kidney Neoplasms , Wilms Tumor , Animals , Humans , Apoptosis , Cell Line, Tumor , Cell Proliferation , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Pyroptosis/genetics , RNA, Messenger/genetics , Wilms Tumor/genetics , Wilms Tumor/pathology , Aquaporin 1/geneticsABSTRACT
PURPOSE: Wilms' tumor (WT) is a rare kidney cancer that primarily affects children. Exosomes are extracellular vesicles that cargo nucleic acids, proteins,etc. for cellular communication. Long non-coding RNAs (lncRNAs) have utility as biomarkers for cancer diagnosis, prognosis, and disease monitoring. We hypothesize that expression of lncRNA, metastasis-associated lung adenocarcinoma transcript-1(MALAT1), is dysregulated and possibly trafficked within exosomes to influence the tissue microenvironment for metastasis and recurrence of WT. METHODS: We investigated the expression of MALAT1 in thirty WT samples by qPCR. Exosomes were isolated using a precipitated and affinity-binding-based kit, and characterized using TEM, NTA, and DLS. RESULTS: Mean number of exosomes was 9.01×108/mL in primary culture, 1.64×108/mL in urine, and 4.65×108/plasma:400µl. Average yield of total RNA was 1.28µg (primary-culture supernatant:1ml), 1.47µg (Urine:1ml), 1.65µg (Plasma:400 µL). We quantified MALAT1 in exosomes derived from these sources in patients of WT. Expression of MALAT1 was significantly downregulated (p=0.008) in WT samples. CONCLUSION: This is the first study that demonstrated the presence of lncRNA MALAT1 in various invasive and non-invasive samples of patients with WT(primary tissue culture, urine, and plasma samples).
Subject(s)
Exosomes , Kidney Neoplasms , RNA, Long Noncoding , Wilms Tumor , Child , Humans , RNA, Long Noncoding/genetics , Wilms Tumor/genetics , Kidney Neoplasms/genetics , Liquid Biopsy , Exosomes/genetics , Tumor MicroenvironmentABSTRACT
BACKGROUND: To review race and ethnic group enrollment and outcomes for Wilms tumor (WT) across all 4 risk-assigned therapeutic trials from the current era Children's Oncology Group Renal Tumor Biology and Risk Stratification Protocol, AREN03B2. STUDY DESIGN: For patients with WT enrolled in AREN03B2 (2006 to 2019), disease and biologic features, therapeutic study-specific enrollment, and event-free (EFS) and overall (OS) 4-year survival were compared between institutionally reported race and ethnic groups. RESULTS: Among 5,146 patients with WT, no statistically significant differences were detected between race and ethnic groups regarding subsequent risk-assigned therapeutic study enrollment, disease stage, histology, biologic factors, or overall EFS or OS, except the following variables: Black children were older and had larger tumors at enrollment, whereas Hispanic children had lower rates of diffuse anaplasia WT and loss of heterozygosity at 1p. The only significant difference in EFS or OS between race and ethnic groups was observed among the few children treated for diffuse anaplasia WT with regimen UH-1 and -2 on high-risk protocol, AREN0321. On this therapeutic arm only, Black children showed worse EFS (hazard ratio = 3.18) and OS (hazard ratio = 3.42). However, this finding was not replicated for patients treated with regimen UH-1 and -2 under AREN03B2 but not on AREN0321. CONCLUSIONS: Race and ethnic group enrollment appeared constant across AREN03B2 risk-assigned therapeutic trials. EFS and OS on these therapeutic trials when analyzed together were comparable regarding race and ethnicity. Black children may have experienced worse stage-specific survival when treated with regimen UH-1 and -2 on AREN0321, but this survival gap was not confirmed when analyzing additional high-risk AREN03B2 patients.