MicroRNAs Possibly Involved in the Development of Bone Metastasis in Clear-Cell Renal Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Kinget L
PROVIDER: S-EPMC8036650 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Clear cell renal cell carcinoma (ccRCC) is the most common and lethal renal malignant tumor in adults. The aim of the present study was to identify the key genes involved in ccRCC metastasis. Expression profiling data for ccRCC patients with metastasis and without metastasis were obtained from The Cancer Genome Atlas database. The datasets were used to identify differentially expressed genes (DEGs) between the metastasis group and the non-metastasis group using the DESeq2 package. Function enrichment analyses of DEGs were performed. The protein-protein interaction (PPI) network was constructed and analyzed using the Search Tool for the Retrieval of Interacting Genes and Cytoscape for further analysis of the identified hub genes. A total of 472 DEGs were identified, including 247 that were upregulated and 225 that were downregulated in the metastasis group. Gene Ontology enrichment analysis revealed that DEGs were mainly enriched in cell transmembrane movement and mitotic cell cycle process. Kyoto Encyclopedia of Genes Genomes pathway analysis revealed that the DEGs were mainly involved in the 'cell cycle' (hsa04110), 'collecting duct acid secretion' (hsa04966), 'complement and coagulation cascades' (hsa04610) and 'aldosterone-regulated sodium reabsorption' (hsa04960) pathways. Using the PPI network, 35 hub genes were identified, and the majority of them were upregulated in ccRCC tissue compared with normal kidney tissue. The expression levels of certain hub genes (CDKN3, TPX2, BUB1B, CDCA8, UBE2C, NDC80, RRM2, NCAPG, NCAPH, PTTG1, FAM64A, ANLN, KIF4A, CEP55, CENPF, KIF20A, ASPM and HJURP) were significantly associated with overall survival and recurrence-free survival in ccRCC. The present study has identified key genes associated with the metastasis of ccRCC.
| S-EPMC6447949 | biostudies-literature
Project description:IntroductionRenal cell carcinoma (RCC) is one of the most common malignancies globally, among which clear cell carcinoma (ccRCC) accounts for 85-90% of all pathological types. This study aims to screen out potential genes in metastatic ccRCC so as to provide novel insights for ccRCC treatment.MethodsGSE53757 and GSE84546 datasets in the Gene Expression Omnibus (GEO) were profiled to identify differentially expressed genes (DEGs) from ccRCC samples with or without metastasis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and the gene ontology (GO) analysis were performed to analyze pathway enrichment and functional annotation of DEGs. Protein-protein interaction (PPI) network was constructed, and survival analysis was conducted to evaluate the clinical values of the identified hub genes. In vitro loss-of-function assays were performed to explore the biological roles of these genes.ResultsThe bioinformatic analysis indicated that 312 DEGs were identified, including 148 upregulated genes and 164 downregulated ones. Using PPI and Cytoscape, 10 hub genes were selected (C3, CXCR4, CCl4, ACKR3, KIF20A, CCNB2, CDCA8, CCL28, S1PR5, and CCL20) from DEGs which might be closely related with ccRCC metastasis. In Kaplan-Meier analysis, three potential prognostic biomarkers (KIF20A, CCNB2 and CDCA8) were identified. Finally, cell proliferative and invasive assays further verified that KIF20A, CCNB2 and CDCA8 were associated with the proliferation and invasion of ccRCC cells.ConclusionOur results demonstrated that metastatic ccRCC was partially attributed to the aberrant expression of KIF20A, CCNB2 and CDCA8, and more personalized therapeutic approaches should be explored targeting these hub genes.
| S-EPMC7779301 | biostudies-literature
Project description: Not available
| S-DIXA-D-1153 | biostudies-other
Project description:MicroRNAs (miRNAs) play a pivotal role in cancerogenesis and cancer progression, but their specific role in the metastasis of clear cell renal cell carcinomas (ccRCC) is still limited. Based on microRNA microarray analyses from normal and cancerous samples of ccRCC specimens and from bone metastases of ccRCC patients, we identified a set of 57 differentially expressed microRNAs between these three sample groups of ccRCC. A selected panel of 33 miRNAs was subsequently validated by RT-qPCR on total 57 samples. Then, 30 of the 33 examined miRNAs were confirmed to be deregulated. A stepwise down-regulation of miRNA expression from normal, over primary tumor to metastatic tissue samples, was found to be typical. A total of 23 miRNAs (miR-10b/-19a/-19b/-20a/-29a/-29b/-29c/-100/-101/-126/-127/-130/-141/-143/-145/-148a/-192/-194/-200c/-210/-215/-370/-514) were down-regulated in metastatic tissue samples compared with normal tissue. This down-regulated expression in metastatic tissue in comparison with primary tumor tissue was also present in 21 miRNAs. In cell culture experiments with 5-aza-2'-deoxycytidine and trichostatin A, epigenetic modifications were shown as one reason of this down-regulation. The altered miRNA profiles, comprising newly identified metastasis-associated miRNAs, termed metastamir and the predicted miRNA-target interactions together with the significant correlations of miRNAs that were either lost or newly appeared in the studied sample groups, afford a solid basis for further functional analyses of individual miRNAs in RCC metastatic progression.
| S-EPMC3492794 | biostudies-literature
Project description:Bone metastasis is an important prognostic factor in renal cell carcinoma (RCC). The calcium-sensing receptor (CaSR) has been associated with bone metastasis in several different malignancies. We analyzed the impact of CaSR in bone metastasis in RCC in vitro and in vivo. The RCC cell line 786-O was stably transfected with the CaSR gene and treated with calcium alone or in combination with the CaSR antagonist NPS2143. Afterwards migration, adhesion, proliferation and prominent signaling molecules were analyzed. Calcium treated CaSR-transfected 768-O cells showed an increased adhesion to endothelial cells and the extracellular matrix components fibronectin and collagen I, but not to collagen IV. The chemotactic cell migration and proliferation was also induced by calcium. The activity of SHC, AKT, ERK, P90RSK and JNK were enhanced after calcium treatment of CaSR-transfected cells. These effects were abolished by NPS2143. Development of bone metastasis was evaluated in vivo in a mouse model. Intracardiac injection of CaSR-transfected 768-O cells showed an increased rate of bone metastasis. The results indicate CaSR as an important component in the mechanism of bone metastasis in RCC. Therefore, targeting CaSR might be beneficial in patients with bone metastatic RCC with a high CaSR expression.
| S-EPMC5884663 | biostudies-literature
Project description:Bone is one of the common sites of metastases from renal cell carcinoma (RCC), however the mechanism by which RCC preferentially metastasize to bone is poorly understood. Homing/retention of RCC cells to bone and subsequent proliferation are necessary steps for RCC cells to colonize bone. To explore possible mechanisms by which these processes occur, we used an in vivo metastasis model in which 786-O RCC cells were injected into SCID mice intracardially, and organotropic cell lines from bone, liver, and lymph node were selected. The expression of molecules affecting cell adhesion, angiogenesis, and osteolysis were then examined in these selected cells. Cadherin-11, a mesenchymal cadherin mainly expressed in osteoblasts, was significantly increased on the cell surface in bone metastasis-derived 786-O cells (Bo-786-O) compared to parental, liver, or lymph node-derived cells. In contrast, the homing receptor CXCR4 was equivalently expressed in cells derived from all organs. No significant difference was observed in the expression of angiogenic factors, including HIF-1α, VEGF, angiopoeitin-1, Tie2, c-MET, and osteolytic factors, including PTHrP, IL-6 and RANKL. While the parental and Bo-786-O cells have similar proliferation rates, Bo-786-O cells showed an increase in migration compared to the parental 786-O cells. Knockdown of Cadherin-11 using shRNA reduced the rate of migration in Bo-786-O cells, suggesting that Cadherin-11 contributes to the increased migration observed in bone-derived cells. Immunohistochemical analysis of cadherin-11 expression in a human renal carcinoma tissue array showed that the number of human specimens with positive cadherin-11 activity was significantly higher in tumors that metastasized to bone than that in primary tumors. Together, these results suggest that Cadherin-11 may play a role in RCC bone metastasis.
| S-EPMC3933681 | biostudies-literature
Project description:BackgroundWith the advent of second-generation sequencing, the expression of gene transcripts can be digitally measured with high accuracy. The purpose of this study was to systematically profile the expression of both mRNA and miRNA genes in clear cell renal cell carcinoma (ccRCC) using massively parallel sequencing technology.MethodologyThe expression of mRNAs and miRNAs were analyzed in tumor tissues and matched normal adjacent tissues obtained from 10 ccRCC patients without distant metastases. In a prevalence screen, some of the most interesting results were validated in a large cohort of ccRCC patients.Principal findingsA total of 404 miRNAs and 9,799 mRNAs were detected to be differentially expressed in the 10 ccRCC patients. We also identified 56 novel miRNA candidates in at least two samples. In addition to confirming that canonical cancer genes and miRNAs (including VEGFA, DUSP9 and ERBB4; miR-210, miR-184 and miR-206) play pivotal roles in ccRCC development, promising novel candidates (such as PNCK and miR-122) without previous annotation in ccRCC carcinogenesis were also discovered in this study. Pathways controlling cell fates (e.g., cell cycle and apoptosis pathways) and cell communication (e.g., focal adhesion and ECM-receptor interaction) were found to be significantly more likely to be disrupted in ccRCC. Additionally, the results of the prevalence screen revealed that the expression of a miRNA gene cluster located on Xq27.3 was consistently downregulated in at least 76.7% of ?50 ccRCC patients.ConclusionsOur study provided a two-dimensional map of the mRNA and miRNA expression profiles of ccRCC using deep sequencing technology. Our results indicate that the phenotypic status of ccRCC is characterized by a loss of normal renal function, downregulation of metabolic genes, and upregulation of many signal transduction genes in key pathways. Furthermore, it can be concluded that downregulation of miRNA genes clustered on Xq27.3 is associated with ccRCC.
| S-EPMC3013074 | biostudies-literature
Project description:BackgroundMetastasis is the main cause of treatment failure in various cancer, including ccRCC. However, the key genes involved in ccRCC metastasis remain largely unknown.PurposeThe identification of the aberrant gene expression patterns associated with metastatic traits is of great clinical significance. The aim of this study was to investigate the clinical significance and function of PDE7B in ccRCC.Materials and methodsExpression profiling data for patient-matched primary and metastatic ccRCC tumors were obtained from GEO Dataset. Limma package was used to identify differentially expressed genes (DEGs) between the metastatic and the primary groups. Gene Ontology, Kyoto Encyclopedia of Genes Genomes (KEGG), and PPI network analysis were used to study the interacting activities and the interconnection of the DEGs. CCK-8 assays and Transwell assays were performed to detect the proliferation and migration of renal cancer cells.ResultsWe obtained 163 DEGs, including 132 that were upregulated and 31 that were downregulated in metastatic ccRCC tissues. Both Gene Ontology function and KEGG pathway analysis showed that DEGs were involved in extracellular matrix (ECM) organization and cell adhesion. After utilizing PPI network to explore the interconnection among the DEGs, 22 genes were selected as the hub genes. Subsequently, survival analysis revealed that seven hub genes (SFN, NKX2-1, HP, MAPT, EPHA4, KCNAB1, and PDE7B) were significantly associated with overall survival disease-specific survival, and progression-free interval in ccRCC. Moreover, the low expression of PDE7B was found in clinical ccRCC samples and correlated with TNM stage and histologic grade. We further showed that knockdown of PDE7B increased cell growth and migration of renal cancer cells.ConclusionOur results implicated that PDE7B may play a key role in the development of metastatic RCC.
| S-EPMC7367933 | biostudies-literature
Project description:About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastases. The incidence of RCC is increasing and bone metastatic RCC merits greater focus. Realistic preclinical bone metastasis models of RCC are lacking, hampering the development of effective therapies. We developed a realistic in vivo bone metastasis model of human RCC by implanting precision-cut tissue slices under the renal capsule of immunodeficient mice. The presence of disseminated cells in bone marrow of tissue slice graft (TSG)-bearing mice was screened by human-specific polymerase chain reaction and confirmed by immunohistology using human-specific antibody. Disseminated tumor cells in bone marrow of TSG-bearing mice derived from three of seven RCC patients were detected as early as 1 month after tissue implantation at a high frequency with close resemblance to parent tumors (e.g., CAIX expression and high vascularity). The metastatic patterns of TSGs correlated with disease progression in patients. In addition, TSGs retained capacity to metastasize to bone at high frequency after serial passaging and cryopreservation. Moreover, bone metastases in mice responded to Temsirolimus treatment. Intratibial injections of single cells generated from TSGs showed 100 % engraftment and produced X-ray-visible tumors as early as 3 weeks after cancer cell inoculation. Micro-computed tomography (?CT) and histological analysis revealed osteolytic characteristics of these lesions. Our results demonstrated that orthotopic RCC TSGs have potential to develop bone metastases that respond to standard therapy. This first reported primary RCC bone metastasis model provides a realistic setting to test therapeutics to prevent or treat bone metastases in RCC.
| S-EPMC4351963 | biostudies-literature
Project description:B7 homolog 3 (B7-H3) plays an important role in tumor biology, but the molecular mechanism underlying the role of B7-H3 in tumor metastasis remains unclear. In this article, our analysis of The Cancer Genome Atlas database suggested that B7-H3 expression is associated with poor prognosis of patients with clear cell renal cell carcinoma (ccRCC). B7-H3 knockdown affected the expression of metastasis-related genes and significantly suppressed the metastasis of ccRCC cells, but it had no significant effect on the proliferation of ccRCC cells. Database analysis revealed a strong positive correlation between B7-H3 and fibronectin (FN) in ccRCC cells, and further study also confirmed that FN interacts with B7-H3. Silencing FN expression inhibited the migration and invasion of ccRCC cells, whereas exogenous FN promoted the migration and invasion of ccRCC cells, which was accompanied by activation of kinases [namely, phosphorylated (p)-phosphoinositide 3-kinase, p-protein kinase B, p-p38 and p-extracellular regulated protein kinase]. B7-H3 knockdown abolished the prometastatic effect of FN. In conclusion, our data suggest that B7-H3 binds to exogenous FN and promotes the metastasis of ccRCC cells.
| S-EPMC8564341 | biostudies-literature