Study on HOXBs of Clear Cell Renal Cell Carcinoma and Detection of New Molecular Target.
Ontology highlight
ABSTRACT:
SUBMITTER: Wu G
PROVIDER: S-EPMC8282400 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Background and Objective: Epigenetic alterations are common events in clear cell renal cell carcinoma (ccRCC), and protein arginine methyltransferase 1 (PRMT1) is an important epigenetic regulator in cancers. However, its role in ccRCC remains unclear. Methods: We investigated PRMT1 expression level and its correlations to clinicopathological factors and prognosis in ccRCC patients based on ccRCC tissue microarrays (TMAs). Genetic knockdown and pharmacological inhibition using a novel PRMT1 inhibitor DCPT1061 were performed to investigate the functional role of PRMT1 in ccRCC proliferation. Besides, we confirmed the antitumor effect of PRMT1 inhibitor DCPT1061 in ccRCC cell-derived tumor xenograft (CDX) models as well as patient-derived tumor xenograft (PDX) models. Results: We found PRMT1 expression was remarkably upregulated in tumor tissues and associated with poor pathologic characters and outcomes of ccRCC patients. Furthermore, genetic knockdown and pharmacological inhibition of PRMT1 by a novel potent inhibitor DCPT1061 dramatically induced G1 cell cycle arrest and suppressed ccRCC cell growth. Mechanistically, RNA sequencing and further validation identified Lipocalin2 (LCN2), a secreted glycoprotein implicated in tumorigenesis, as a crucial regulator of ccRCC growth and functional downstream effector of PRMT1. Epigenetic silencing of LCN2 autocrine secretion by PRMT1 deficiency decreased downstream p-AKT, leading to reduced p-RB and cell growth arrest through the neutrophil gelatinase associated lipocalin receptor (NGALR). Moreover, PRMT1 inhibition by DCPT1061 not only inhibited tumor growth but also sensitized ccRCC to sunitinib treatment in vivo by attenuating sunitinib-induced upregulation of LCN2-AKT-RB signaling. Conclusion: Taken together, our study revealed a PRMT1-dependent epigenetic mechanism in the control of ccRCC tumor growth and drug resistance, indicating PRMT1 may serve as a promising target for therapeutic intervention in ccRCC patients.
| S-EPMC8039964 | biostudies-literature
Project description:Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRCC using targeted panel sequencing including patients with microdissected sarcomatoid and epithelial components. Along with common genomic alterations associated with clear-cell histology, we found that Hippo was one of the most frequently altered pathways in these tumours. Hippo alterations were differentially enriched in sRCC compared to non-sRCC. Functional analysis showed that Hippo members mutations were associated with higher nuclear accumulation of YAP/TAZ, core effectors of the Hippo pathway. In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo. Overall, we show that Hippo pathway alterations are a feature of sRCC, and enable the exploration of the Hippo pathway as a novel potential therapeutic target.
| S-EPMC6971072 | biostudies-literature
Project description:Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.
| S-EPMC3771322 | biostudies-literature
Project description:We set out to identify Stearoyl-CoA desaturase 1 (SCD1) as a novel molecular target in clear cell renal cell carcinoma (ccRCC) and examine its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current U.S. Food and Drug Administration (FDA)-approved regimens.Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor, A939572, were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus.Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of A939572-treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of A939572 with temsirolimus synergistically inhibited tumor growth in vitro and in vivo.Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease.
| S-EPMC3644999 | biostudies-literature
Project description:There is a need for accurate and rapid detection of renal cancer in clinic. Here, we integrated photoacoustic tomography (PAT) with ultrasound imaging in a single system, which achieved tissue imaging depth about 3 mm and imaging speed about 3.5 cm2/min. We used the wavelength at 1197 nm to map lipid distribution in normal renal tissues and clear cell renal cell carcinoma (ccRCC) tissues collected from 19 patients undergone nephrectomy. Our results indicated that the photoacoustic signal from lipids was significantly higher in ccRCC tissues than that in normal tissues. Moreover, based on the quantification of lipid area ratio, we were able to differentiate normal and ccRCC with 100 % sensitivity, 80 % specificity, and area under receiver operating characteristic curve of 0.95. Our findings demonstrate that multimodal PAT can differentiate normal and ccRCC by integrating the morphologic information from ultrasound and lipid amount information from vibrational PAT.
| S-EPMC7683266 | biostudies-literature
Project description:Gasdermin (GSDM) family members are involved in numerous biological processes, including pyroptosis, as well as in the initiation and progression of various types of cancer. However, the specific role of GSDM genes in clear cell renal cell carcinoma (ccRCC) has yet to be fully clarified. The present study investigated the differential expression and genetic alterations GSDM genes, their effects on prognosis and immune modulation, and their functional enrichment in ccRCC. Several bioinformatics databases were used, including UALCAN, The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, Metascape, Tumor Immune Estimation Resource, GSCALite and cBioPortal. The results revealed that the expression levels of GSDMA, GSDMB, GSDMC and GSDMD were significantly upregulated in cancer tissues compared with those in paracancerous tissues in patients with ccRCC, whereas the expression of DFNB59 exhibited the opposite trend. The results were experimentally validated in patients with ccRCC, and it was confirmed that the expression levels of GSDMA, GSDMB, GSDMC, GSDMD and GSDME (DFNA5) were significantly enhanced, whereas (PJVK, DFNB59) expression was reduced. In addition, elevated GSDMB, GSDMD and DFNA5 expression levels were clearly associated with worse pathological characteristics of ccRCC, including a high pathological stage and high tumor grade. Furthermore, the high expression levels of GSDMB, GSDMC, GSDMD, DFNA5 and PJVK were shown to be associated with worse overall survival (OS) and progression-free interval in patients with ccRCC. Both univariate and multivariate analyses indicated that the expression of GSDMB was independently associated with the OS of patients with ccRCC. Additionally, a high mutation rate of GSDM genes (33%) was observed in patients with ccRCC, and GSDM gene mutations were also significantly associated with a poor OS in patients with ccRCC. Significant associations between GSDM genes and ccRCC immunoprofiling and drug sensitivity were also determined. In conclusion, the findings of the present study indicated that GSDMB, GSDMD and DFNA5 may be considered promising therapeutic agents and potential biomarkers for patients with ccRCC. Furthermore, GSDMB could act as an independent predictor for the OS of patients with ccRCC.
| S-EPMC10797315 | biostudies-literature
Project description:We previously reported that the pVHL-atypical PKC-JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (ccRCC), and we detected chemokine (C-C motif) ligand-2 (CCL2) as one of downstream effectors of JunB. CCL2 plays a critical role in tumorigenesis in other types of cancer, but its role in ccRCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL2 in ccRCC. Immunohistochemical analysis of CCL2 expression for ccRCC specimens showed that upregulation of CCL2 expression correlated with clinical stage, overall survival, and macrophage infiltration. For functional analysis of CCL2 in ccRCC cells, we generated subclones of WT8 cells that overexpressed CCL2 and subclones 786-O cells in which CCL2 expression was knocked down. Although CCL2 expression did not affect cell proliferation in vitro, CCL2 overexpression enhanced and CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo. We then depleted macrophages from tumor xenografts by administration of clodronate liposomes to confirm the role of macrophages in ccRCC. Depletion of macrophages suppressed tumor growth and angiogenesis. To examine the effect of inhibiting CCL2 activity in ccRCC, we administered CCL2 neutralizing antibody to primary RCC xenografts established from patient surgical specimens. Inhibition of CCL2 activity resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration. These results suggest that CCL2 is involved in angiogenesis and macrophage infiltration in ccRCC, and that CCL2 could be a potential therapeutic target for ccRCC.
| S-EPMC5083746 | biostudies-literature
Project description:Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma. Redox metabolism has been recognized as the hallmark of cancer. But the concrete role of redox-related genes in patient stratification of ccRCC remains unknown. Herein, we aimed to characterize the molecular features of ccRCC based on the redox gene expression profiles from The Cancer Genome Atlas. Differentially expressed redox genes (DERGs) and vital genes in metabolism regulation were identified and analyzed in the ccRCC. Consensus clustering was performed to divide patients into three clusters (C1, C2, and C3) based on 139 redox genes with median FPKM value > 1. We analyzed the correlation of clusters with clinicopathological characteristics, immune infiltration, gene mutation, and response to immunotherapy. Subclass C1 was metabolic active with moderate prognosis and associated with glucose, lipid, and protein metabolism. C2 had intermediate metabolic activity with worse prognosis and correlated with more tumor mutation burden, neoantigen, and aneuploidy, indicating possible drug sensitivities towards immune checkpoint inhibitors. Metabolic exhausted subtype C3 showed high cytolytic activity score, suggesting better prognosis than C1 and C2. Moreover, the qRT-PCR was performed to verify the expression of downregulated DERGs including ALDH6A1, ALDH1L1, GLRX5, ALDH1A3, and GSTM3, and upregulated SHMT1 in ccRCC. Overall, our study provides an insight into the characteristics of molecular classification of ccRCC patients based on redox genes, thereby deepening the understanding of heterogeneity of ccRCC and allowing prediction of prognosis of ccRCC patients.
| S-EPMC8799361 | biostudies-literature
Project description:The lack of symptoms at the early stages of clear cell renal cell carcinoma (ccRCC) allows the tumour to metastasize, leading to a dramatic reduction in patient survival. Therefore, we studied and set up a method based on urinary microRNAs (miRNAs) for the diagnosis of ccRCC. First, miRNA expression in ccRCC specimens and kidney tissues from healthy subjects (HSs) was investigated through analysis of data banks and validated by comparing expression of miRNAs in ccRCC and adjacent non-cancerous kidney tissue specimens by RT-qPCR. Subsequently, we developed an algorithm to establish which miRNAs are more likely to be found in the urine of ccRCC patients that indicated miR-122, miR-1271, and miR-15b as potential interesting markers. The evaluation of their levels and three internal controls in the urine of 13 patients and 14 HSs resulted in the development of a score (7p-urinary score) to evaluate the presence of ccRCC in patients. The resulting area under the Receiver Operating Characteristic (ROC) curve, sensitivity, and specificity were equal to 0.96, 100% (95% CI 75-100%), and 86% (95% CI 57-98%), respectively. In conclusion, our study provides a proof of concept that combining the expression values of some urinary miRNAs might be useful in the diagnosis of ccRCC.
| S-EPMC7718885 | biostudies-literature
Project description:Clear cell papillary renal cell carcinoma (CCPRCC) is a low-grade renal neoplasm with morphological characteristics mimicking both clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). However, despite some overlapping features, their morphological, immunohistochemical, and molecular profiles are distinct. Micro-RNAs (miRNAs) are small noncoding RNAs that play a crucial role in regulating gene expression and are involved in various biological processes, including cancer development. To better understand the biology of this tumor, we aimed to analyze the miRNA expression profile of a set of CCPRCC using microarray and quantitative reverse transcription-polymerase chain reaction. A total of 15 cases diagnosed as CCPRCC were used in this study. Among the most differentially expressed miRNA in CCPRCC, we found miR-210, miR-122, miR-34a, miR-21, miR-34b*, and miR-489 to be up-regulated, whereas miR-4284, miR-1202, miR-135a, miR-1973, and miR-204 were down-regulated compared with normal renal parenchyma. To identify consensus of differentially regulated miRNA between CCPRCC, CCRCC, and PRCC, we additionally determined differential miRNA expression using 2 publically available microarray data sets from the NCBI Gene Expression Omnibus database (GSE41282 and GSE3798). This comparison revealed that the miRNA expression profile of CCPRCC shows some overlapping characteristics between CCRCC and PRCC. Moreover, CCPRCC lacks dysregulation of important miRNAs typically associated with aggressive behavior. In summary, we describe the miRNA expression profile of a relatively infrequent type of renal cancer. Our results may help in understanding the molecular underpinning of this newly recognized entity.
| S-EPMC4332813 | biostudies-literature