Overexpression of SATB1 is associated with biologic behavior in human renal cell carcinoma.
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ABSTRACT:
SUBMITTER: Cheng C
PROVIDER: S-EPMC4023980 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There is increasing evidence that Special AT-rich sequence-binding protein 1 (SATB1) is aberrantly expressed in several cancers and is correlated with clinicopathologic parameters in these tumors. In this study, we showed over-expression of SATB1 in 80 cases of colorectal cancer and in 3 colorectal cancer cell lines and found expression levels were strongly associated with tumor differentiation and stage. Expression levels of SATB1 protein were higher in poorly-differentiated as compared with well-differentiated cell lines, and both quantity and distribution patterns of SATB1 were associated with tumor differentiation and pTNM stage. Strikingly, we further investigated the effect of down regulation of SATB1 expression on malignant phenotypic features in colorectal cancer cells in vitro, and showed that SABT1 down-regulation negatively affected growth potential, anchorage-independent colony formation and cancer cell invasion, and resulted in increased apoptosis. SATB1 expression was positively associated with the expression of various biological and genetic markers, including Cyclin D1, MMP-2, NF-?B, and PCNA, and was associated with loss of APC and BRAF(V600E). These findings suggest that SATB1 is involved in the carcinogenesis, development and progression of colorectal cancer.
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Project description:ObjectivesNever in mitosis gene A-related kinase 2 (NEK2) has been implicated in tumorigenesis in various tissues, but its function in clear cell renal cell carcinoma (ccRCC) tumorigenesis is unclear. We evaluated the correlation between NEK2 expression and ccRCC.MethodsImmunohistochemistry analysis of NEK2 protein was done on high-density multi-organ Human Cancer tissue microarray derived from the patient samples from clear cell renal cell carcinoma. We used multiple clinical cohorts to analyze the NEK2 immunohistochemical staining expression across human cancers. The cancer genome atlas (TCGA) data analysis of NEK2 was done through UALCAN web servers. Association of NEK2 and Kaplan-Meier survival analysis was done on both of our clinical database and available TCGA datasets.ResultsUsing the UALCAN cancer transcriptional data analysis website, we found that NEK2 is overexpressed in ccRCC, and its expression was associated with overall survival. According to the analyses of our own clinical database and immunohistochemical staining, protein levels of NEK2 were elevated in renal carcinoma compared to adjacent normal tissues. Kaplan-Meier survival analysis of both UALCAN and our database showed that high expression of NEK2 was associated with a poor prognosis. Multivariate and univariate analyses showed that NEK2 expression was closely related to a poor prognosis. The findings suggest that NEK2 is associated with ccRCC.ConclusionThese studies show that NEK2 is over-expressed in clear cell renal cell carcinoma and plays an essential role in cancer cell survival, as such NEK2 could serve as a novel potential target for therapeutic intervention in ccRCC.
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Project description:Special AT-rich sequence-binding protein 1 (Satb1) governs genome-wide transcriptional programs. Using a conditional knockout mouse, we find that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating major histocompatibility complex class II (MHC II) expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46(+) inflammatory DCs that infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. In vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but continuous Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.
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Project description:BackgroundTryptophan 2,3-dioxygenase (TDO2) is the primary enzyme catabolizing tryptophan. Several lines of evidence revealed that overexpression of TDO2 is involved in anoikis resistance, spheroid formation, proliferation, and invasion and correlates with poor prognosis in some cancers. The aim of this research was to uncover the expression and biofunction of TDO2 in renal cell carcinoma (RCC).MethodsTo show the expression of TDO2 in RCC, we performed qRT-PCR and immunohistochemistry in integration with TCGA data analysis. The interaction of TDO2 with PD-L1, CD44, PTEN, and TDO2 expression was evaluated. We explored proliferation, colony formation, and invasion in RCC cells line affected by knockdown of TDO2.ResultsRNA-Seq and immunohistochemical analysis showed that TDO2 expression was upregulated in RCC tissues and was associated with advanced disease and poor survival of RCC patients. Furthermore, TDO2 was co-expressed with PD-L1 and CD44. In silico analysis and in vitro knockout of PTEN in RCC cell lines revealed the ability of PTEN to regulate the expression of TDO2. Knockdown of TDO2 suppressed the proliferation and invasion of RCC cells.ConclusionOur results suggest that TDO2 might have an important role in disease progression and could be a promising marker for targeted therapy in RCC. (199 words).
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Project description:Clear-cell renal cell carcinoma (ccRCC) is the most prevalent renal malignancy. The pathogenesis of the disease is currently poorly understood, and the prognosis is poor. Therefore, in this study, we focused on exploring and identifying genes and signal transduction pathways that are closely related to ccRCC. Differentially expressed genes (DEGs) were analyzed using the renal cell oncogene expression profiles GSE100666 and GSE68417. DAVID evaluation of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses was used. We constructed a protein-protein interaction (PPI) network of DEGS using Cytoscape software and analyzed the submodules with the CytoHubba plugin. Finally, we performed western blot, immunohistochemistry, and PCR validation by collecting tissues, and also utilized cells for in vitro functional analysis of ceruloplasmin (CP). In total, 202 DEGs (52 upregulated and 150 downregulated genes) were identified. Upregulated DEGs are significantly rich in angiogenesis, cell adhesion, and response to hypoxia, whereas downregulated DEGs are involved in intracellular pH regulation, excretion, coagulation, and chloride transmembrane transport. We selected the interactions of the top 20 hub genes provided by the PPI network, all of which are involved in important physiological pathways in vivo, such as complement and coagulation cascades. Tissue protein assays demonstrated that renal cancer highly expressed CP, while in vitro experiments showed that CP could promote the invasion of renal cancer cells. Our study suggests that ALB, C3, LOX, HRG, CXCR4, GPC3, SLC12A3, CP, and CASR may be involved in the development of ccRCC, and is expected to provide theoretical support for future studies on the diagnosis and targeted therapy of ccRCC.
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Project description:Clear cell renal cell carcinoma (ccRCC) is the highest mortality, invasion, and metastasis subtype of renal cell carcinoma. Bone morphogenetic protein (BMP) family has recently emerged as a group of cancer-related proteins in multiple pathogenesis of cancers. Currently, little is known about the prediction role of BMPs in ccRCC. Therefore, we screened The Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) database for ccRCC patients with complete clinical information and BMP family expression data. Multivariate analysis showed that high expression of BMP1 was associated with shorter overall survival (OS) (P?=?0.001), and shorter disease-free survival (DFS) (P?=?0.018). Gene set enrichment analysis (GSEA) showed BMP1 was associated with epithelial-mesenchymal transition (EMT), G2M checkpoint, angiogenesis, hypoxia pathway, and Kirsten rat sarcoma viral oncogene (KRAS) signaling. Knockdown BMP1 suppressed malignancy of ccRCC in vitro and in vivo. Our results indicated that high expressions of BMP1 were poor prognostic factors and gene therapy could be an effective treatment for ccRCC.
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Project description:BackgroundGrowing findings have demonstrated that interferon regulatory transcription factor (IRF) family members are linked to the progression of various cancers. However, the roles of IRFs in clear cell renal cell carcinoma (ccRCC) remain undefined. Herein, we conducted a comprehensive analysis using the bioinformatics method to evaluate the expression patterns, clinical significance, and regulation of IRFs-related mechanisms in patients with ccRCC.MethodsData from the Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGA), and Gene Expression Omnibus (GEO) databases were used for investigation comprehensively. Specifically, we carried out a series of analyses to identify the candidate IRF and to explore its potential action mechanisms using the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. What is more, we emphatically investigate the association of candidate IRF with tumor immunity in ccRCC through the CIBERSORT algorithm, TIMER and GEPIA databases.ResultsHerein, IRF3 was identified as candidate IRF, which was highly expressed in ccRCC, and its overexpression was significantly associated with worse clinical outcomes and adverse overall survival. Uni- and multi-variate Cox regression analysis demonstrated that IRF3 overexpression was an independent predictor of worse prognosis. Functional enrichment analysis showed that IRF3 might participate in several cancer-related biological processes and signaling pathways, thereby promoting the progression of ccRCC. Additionally, we found that IRF3 was remarkably associated with tumor-infiltrating immune cells (TIICs) and various immune-related genes.ConclusionHerein, we identified IRF3 from the IRF gene family members, which could serve as promising prognostic marker and therapeutic target in ccRCC.
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Project description:BackgroundCancer cells prefer utilizing aerobic glycolysis in order to exacerbate tumor mass and maintain un-regulated proliferative rates. As a key glycolytic activator, phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) has been implicated in multiple tumor type progression. However, the specific function and clinical significance of PFKFB3 in renal cell carcinoma (RCC) are yet not clarified. This investigation assessed PFKFB3 roles in RCC.MethodsPFKFB3 expression levels were analyzed in clear cell renal cell carcinoma (ccRCC) tissues, together with its relationship with clinical characteristics of ccRCC. Real-time PCR and Western blot assays were employed for determining PFKFB3 expression in different RCC cell lines. Furthermore, we determined the glycolytic activity by glucose uptake, lactate secretion assay and ECAR analysis. CCK-8 assay, clone formation, flow cytometry and EdU assessments were performed for monitoring tumor proliferative capacity and cell-cycle distribution. Furthermore, a murine xenograft model was employed for investigating the effect of PFKFB3 on tumor growth in vivo.ResultsPFKFB3 was significantly up-regulated in RCC specimens and cell lines in comparison to normal control. Overexpression of PFKFB3 was directly correlated to later TNM stages, thus becoming a robust prognostic biomarker for ccRCC cases. Furthermore, PFKFB3 knockdown suppressed cell glycolysis, proliferative rate and cell-cycle G1/S conversion in RCC cells. Importantly, in vivo experiments confirmed that PFKFB3 knockdown delayed tumor growth derived from the ACHN cell line.ConclusionsSuch results suggest that PFKFB3 is a key molecular player in RCC progression via mediating glycolysis / proliferation and provides a potential therapeutic target against RCC.
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Project description:Neural epidermal growth factor-like like (NELL) 1 and 2 constitute a family of multimeric and multimodular extracellular glycoproteins. Although the osteogenic effects of NELL1 and functions of NELL2 in neural development have been reported, their expression and functions in cancer are largely unknown. In this study, we examined expression of NELL1 and NELL2 in renal cell carcinoma (RCC) using clinical specimens and cell lines. We show that, whereas NELL1 and NELL2 proteins are strongly expressed in renal tubules in non-cancerous areas of RCC specimens, their expression is significantly downregulated in cancerous areas. Silencing of NELL1 and NELL2 mRNA expression was also detected in RCC cell lines. Analysis of NELL1/2 promoter methylation status indicated that the CpG islands in the NELL1 and NELL2 genes are hypermethylated in RCC cell lines. NELL1 and NELL2 bind to RCC cells, suggesting that these cells express a receptor for NELL1 and NELL2 that can transduce signals. Furthermore, we found that both NELL1 and NELL2 inhibit RCC cell migration, and NELL1 further inhibits RCC cell adhesion. These results suggest that silencing of NELL gene expression by promoter hypermethylation plays roles in RCC progression by affecting cancer cell behavior.
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