Tumoral CD105 is a novel independent prognostic marker for prognosis in clear-cell renal cell carcinoma.
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ABSTRACT:
SUBMITTER: Saroufim A
PROVIDER: S-EPMC3974088 | biostudies-other | 2014 Apr
REPOSITORIES: biostudies-other
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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:Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of kidney cancer. We previously reported that CD105(+) subpopulation in human ccRCC tumors possesses tumor cell self-renewal and chemoresistance capability. In this study, we showed that CD105(+) ACHN tumor cells exhibit epithelial mesenchymal transition (EMT) phenotype with high expression of mesenchymal marker N-cadherin and low expression of epithelial marker E-cadherin. They are more motile and invasive compared to the unselected parental ACHN tumor cells. The knockdown of CD105 by RNA interference led to the downregulation of N-cadherin and the upregulation of E-cadherin and reduced motility and invasiveness of CD105(+) cells. Overexpression of stem cell factor MYC in CD105 knocked down cells increased mesenchymal markers and cell motility. However, the CD105(+) population of tumor cells does not exhibit an increase metastatic potential in vivo. Findings from this study support that CD105 plays a functional role in maintaining cancer stem cell and EMT phenotype, with MYC as a common mediator for both of these traits. Our work suggests that the ability to metastasize does not coincide with the cancer stem cell or EMT function of CD105.
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Project description:Exosome-miRNAs (exo-miR) have recently been identified as modulators of cancer progression and distant metastasis. We previously found that intracellular miR-224 is up-regulated and significantly related to cancer invasion and metastasis in clear cell renal cell carcinoma (ccRCC). We therefore investigated the role of exosome miR-224 in ccRCC and explored the interaction between intra- and extracellular miR-224 in renal cell carcinoma. To validate the method for isolating exosomes from blood samples or cell culture media, we examined exosome morphology using transmission electron microscope (TEM). We investigated the relationship between exo-miR-224 expression and patient prognosis in 108 ccRCC patients. We isolated exosomes from a metastatic renal cancer cell line and tested their effects on a primary renal cancer cell line with several functional analyses. We found that the high expression level exo-miR-224 group has significantly shorter progression-free survival, cancer-specific survival, and overall survival compared with the low expression group. In multivariate analysis, a high level of exo-miR-224 was a significant risk factor related to all prognoses investigated. After adding exosomes from a metastatic RCC cell line to a primary RCC cell line, cell proliferation and invasion were increased while the percentage of apoptotic cells was significantly decreased. Intracellular levels of miR-224 were significantly up-regulated in the primary renal cancer cell line. Extracellular miR-224 in exosomes impacts on patient prognosis and is a potential prognostic biomarker for ccRCC patients.
| S-EPMC5746350 | biostudies-literature
Project description:Clear cell renal cell carcinoma (ccRCC) is the most prevalent adult kidney cancer. Prognostic markers are needed to guide patient management toward aggressive versus more conservative approaches, especially for small tumors ?4 cm. miR-194 was reported to be downregulated in several cancers and is involved in epithelial to mesenchymal transition. We evaluated miR-194 as a prognostic marker in ccRCC. In a cohort of 234 patients with primary ccRCC, we correlated miR-194 expression level with multiple clinicopathological features including disease-free and overall survival, tumor size, clinical stage, and histological grade. Our results shows a stepwise decrease in miR-194 expression from normal kidney to primary ccRCC (P = 0.0032) and a subsequent decrease from primary to metastatic lesions. Additionally, patients with higher miR-194 expression has significantly longer disease-free survival (P = 0.041) and overall survival (P = 0.031) compared to those with lower expression. In multivariate analysis, miR-194-positive tumors retain significance in disease-free survival and overall survival, suggesting miR-194 is an independent marker for good prognosis in ccRCC. Moreover, miR-194 is a marker for good prognosis for patients with small renal masses (P = 0.014). These findings were validated on an independent data set from The Cancer Genome Atlas. We also compared miR-194 expression between RCC subtypes. ccRCC had the highest levels, whereas chromophobe RCC and oncocytoma had comparable lower levels. Target prediction coupled with pathway analysis show that miR-194 is predicted to target key molecules and pathways involved in RCC progression. miR-194 represents a prognostic biomarker in ccRCC.
| S-EPMC4831284 | biostudies-literature
Project description:(1). Background: Immunohistochemical (IHC) evaluation of programmed death-1 (PD-1) and its ligand (PD-L1) is being used to evaluate advanced malignancies with potential response to immune checkpoint inhibitors. We evaluated both plasma and tissue expression of PD-1 and PD-L1 in the same cohort of patients, including non-metastatic and metastatic clear cell renal cell carcinoma (CCRCC). Concomitant plasma and tissue expression of PD-1 and PD-L1 was evaluated with emphasis on diagnostic and prognostic implications. (2) Methods: we analyzed PD-1 and PD-L1 IHC expression in tumor tissues and soluble forms (sPD-1 and sPD-L1) in plasma from 89 patients with CCRCC, of which 23 were metastatic and 16 received systemic therapy. The primary endpoint was evaluation of overall survival using Kaplan-Meier analysis and the Cox regression model. Plasma samples from healthy volunteers were also evaluated. (3) Results: Interestingly, sPD-1 and sPD-L1 levels were lower in cancer patients than in controls. sPD-1 and sPD-L1 levels and their counterpart tissue expression both at the tumor center and infiltrating front were not associated. Higher expression of both PD-1 and PD-L1 were associated with tumor grade, necrosis and tumor size. PD-1 was associated to tumor stage (pT) and PD-L1 to metastases. sPD-1 and sPD-L1 were not associated with clinico-pathological parameters, although both were higher in patients with synchronous metastases compared to metachronous ones and sPD-L1 was also higher for metastatic patients compared to non-metastatic patients. sPD-1 was also associated with the International Metastatic Renal Cell Cancer Database Consortium (IMDC) prognostic groups in metastatic CCRCC and also to the Morphology, Attenuation, Size and Structure (MASS) response criteria in metastatic patients treated with systemic therapy, mainly tyrosine-kinase inhibitors. Regarding prognosis, PD-L1 immunostaining at the tumor center with and without the tumor front was associated with worse survival, and so was sPD-L1 at a cut-off >793 ng/mL. Combination of positivity at both the tissue and plasma level increased the level of significance to predict prognosis. (4) Conclusions: Our findings corroborate the role of PD-L1 IHC to evaluate prognosis in CCRCC and present novel data on the usefulness of plasma sPD-L1 as a promising biomarker of survival in this neoplasia.
| S-EPMC7915750 | biostudies-literature
Project description:Renal clear cell carcinoma (ccRCC) is the world's most common form of cancer. Up to a third will develop metastases; the 5-year survival rate of the patients was only 14%. Practical prognostic markers remain to be discovered. Kinesin-like protein (KIFC1), a critical factor in maintaining the stability of the microtubule system, has significant prognostic value in some tumors. We analyzed the prognostic value, associated signaling pathways, and regulatory mechanisms of KIFC1 in ccRCC through bioinformatics and proteomics. Concretely, both mRNA and protein expression levels of KIFC1 were dramatically upregulated. KIFC1 is an independent prognostic factor for ccRCC. The expression of KIFC1 showed a significant positive correlation (Spearman coefficient > 0.7) with tumor proliferation-related pathways (tumor proliferation, G2/M checkpoint, and DNA replication) and tumor inflammation. Further, intratumoral immune cell analysis revealed that high expression of KIFC1 predicted more infiltration of CD8 + T and CD4 + T cells (p < 0.001). However, there was a significant positive relationship between CD8 + T cells and numerous immune checkpoint genes. CD8 + T cells in tumors from the KIFC1 high expression group were at the dysregulated state. High expression of KIFC1 may predict a poor immunotherapy outcome. By proteomics, we analyzed proteins interacting with KIFC1; spliceosome proteins had the most significant enrichment, indicating the new directions for KIFC1 investigation. In conclusion, our study identified KIFC1 as an independent prognostic factor in renal clear cell carcinoma, and the associated processes involved tumor proliferation and immune infiltration. KIFC1 had a close relationship with spliceosome proteins; it may be a new research direction.
| S-EPMC10547834 | biostudies-literature
Project description:BACKGROUND:The majority of patients diagnosed with clear cell renal cell carcinoma (ccRCC) have low-risk disease with a < 10% chance of ccRCC-specific death. DNA sequencing revealed that mutations in BAP1 (BRCA1 associated protein-1) occur in 5% to 15% of ccRCC cases and are associated with poor outcomes. The vast majority of BAP1 mutations abolish protein expression. In this study, we used a highly sensitive and specific immunohistochemistry (IHC) assay to test whether BAP1 expression is an independent marker of ccRCC-specific survival, particularly in patients with low-risk disease. METHODS:BAP1 expression was assessed, using IHC, in 1479 patients who underwent nephrectomy to treat clinically localized ccRCC. A centralized pathologist dichotomized patients as either BAP1-positive or BAP1-negative. The authors employed Kaplan-Meier and Cox regression models to associate BAP1 expression with cancer-specific survival. RESULTS:A total of 10.5% of tumors were BAP1-negative, 84.8% of tumors were BAP1-positive, and 4.6% of tumors had ambiguous staining for BAP1. Patients with BAP1-negative tumors have an increased risk of ccRCC-related death (hazard ratio [HR]?= 3.06; 95% confidence interval [CI]?= 2.28-4.10; P = 6.77 × 10(-14) ). BAP1 expression remained an independent marker of prognosis after adjusting for the UCLA integrated staging system (UISS) (HR = 1.67; 95% CI = 1.24-2.25; P <?.001). Finally, BAP1 was an independent prognostic marker in low-risk patients with a Mayo Clinic stage, size, grade, and necrosis (SSIGN) score of ? 3 (HR = 3.24; 95% CI = 1.26-8.33; P =?.015). CONCLUSIONS:This study used a large patient cohort to demonstrate that BAP1 expression is an independent marker of prognosis in patients with low-risk (SSIGN? 3) ccRCC.
| S-EPMC4075029 | biostudies-literature
Project description:Integrative database analysis was performed to identify novel candidate oncogene AHNAK2 overexpressed in clear cell renal cell carcinoma (ccRCC). However, the function of AHNAK2 in cancer cells is currently unknown. In this study, we first confirmed the upregulation of AHNAK2 in ccRCC tissues compared with adjacent normal tissues in 15 pairs of samples. Then we analyzed AHNAK2 expression in a large cohort of ccRCC patient samples (n = 355), and found that up-regulation of AHNAK2 was positively correlated with tumor progression and poor survival (p = 0.032). Knockdown of AHNAK2 inhibited cancer cell proliferation, colony formation and migration in vitro and tumorigenic ability in vivo. Meanwhile, knockdown of AHNAK2 impaired the cell oncologic-metabolism by inhibiting lipid synthesis. Moreover, we observed that expression of AHNAK2 was greatly upregulated, at least in part, by hypoxia in cancer cells. By using chromatin immune-precipitation (CHIP) and promoter-luciferase reporter assays, we identified that upregulation of AHNAK2 induced by hypoxia was hypoxia-inducible factor-1α (HIF1α)-dependent. Knockdown of AHNAK2 impaired hypoxia-induced epithelial-mesenchymal transition (EMT) and stem cell-like properties. Considered together, we reveal that AHNAK2 is upregulated in cancer cells and hypoxic upregulation of AHNAK2 can drive tumorigenesis and progression by supporting EMT and cancer cell stemness. Thus, AHNAK2 is a novel prognostic marker and an oncogenic protein for ccRCC.
| S-EPMC5399579 | biostudies-literature
Project description:IntroductionClear cell renal cell carcinoma (ccRCC) is the most common type of RCC and is associated with poor survival. However, the mechanisms underlying its development have not been thoroughly investigated. Semaphorin 6D (SEMA6D) is differentially expressed in various cancers, including lung adenocarcinoma and colorectal cancer. However, the role and mechanism of SEMA6D in ccRCC remain unexplored.Materials and methodsWe obtained 25 pairs of ccRCC tissue samples and 57 urine samples from patients with ccRCC and 52 urine samples from healthy volunteers. We performed RNA sequencing and compared the results with data from The Cancer Genome Atlas database to identify our gene of interest, SEMA6D. To verify the differential expression of SEMA6D, we used real-time quantitative polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay. Finally, we conducted in vitro proliferation, migration and invasion experiments.ResultsSEMA6D expression was significantly lower in ccRCC tissue compared to that in normal tissue. Comparative analysis of our results with data from online databases revealed that the expression level of SEMA6D in ccRCC tissue correlated with the clinical stage and pathological grade of ccRCC. Furthermore, higher SEMA6D expression was associated with improved quality of life of patients with ccRCC. In addition, the diagnostic value of SEMA6D was confirmed using data from two Gene Expression Omnibus ccRCC databases. The results showed that SEMA6D can be used as a predictor for ccRCC diagnosis, with an area under the curve of 0.9642.ConclusionSEMA6D may serve as a diagnostic and prognostic biomarker for ccRCC.
| S-EPMC9124703 | biostudies-literature
Project description:BackgroundRenal cell carcinoma (RCC) is a highly vascularised tumour, where anti-angiogenic treatment with multi-tyrosine-kinase-inhibitor, is used for first-line treatment of metastatic disease. Variations in vascular characteristics are likely to contribute to variations in intrinsic aggressiveness of the disease. Emerging studies are identifying perivascular status, including perivascular PDGFR-β, as a determinant of prognosis in other tumour types.MethodsThis work explored the impact on prognosis of vascular characteristics in RCC through analyses of a population-based collection of tumours from surgery-alone-treated patients. The quantitative data from a panel of vascular metrics were obtained through computerised image analysis of sections double-stained for expression of the endothelial cell marker CD34 together with perivascular markers α-SMA or PDGFR-β.ResultsPerivascular expression of PDGFR-β and α-SMA were positively correlated to each other, and negatively correlated to vessel density. High expression of PDGFR-β and α-SMA as well as low vessel density was significantly associated with short survival in uni- and multivariate analyses. Subgroup analyses demonstrated that the prognostic impact of the perivascular markers was particularly prominent in the T4-subgroup. A novel metric, related to PDGFR-β perivascular heterogeneity, was also associated with prognosis in uni-and multi-variate analyses. This novel metric also acted as a prognosis marker in ovarian cancer.ConclusionsThe study demonstrates previously unrecognised associations between RCC survival and the absolute levels, and variability, of perivascular PDGFR-β. This marker should be further explored in other RCC cohorts. Findings also suggest mechanistic analyses and studies on the relationship between perivascular status and efficacy of multi-tyrosine-kinase-inhibitors.
| S-EPMC5243993 | biostudies-literature